Improved daytime spirometric efficacy of tiotropium compared with salmeterol in patients with COPD.

BACKGROUND: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends long-acting bronchodilators as first-line maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). A study was conducted comparing the long-acting anticholinergic tiotropium with the long-acting beta-agonist salmeterol to confirm the significant improvements in daytime bronchodilator efficacy seen with tiotropium in previous studies. METHODS: Randomized, double-blind, double-dummy, parallel-group study, comparing daytime bronchodilator efficacy of tiotropium 18 mcg once daily with salmeterol 50 mcg twice daily in patients with COPD. Serial spirometry was performed over 12 h after 12 weeks of treatment. Co-primary endpoints were average (over 12 h) and peak FEV1 at 12 weeks. RESULTS: 653 patients were randomized (328 tiotropium, 325 salmeterol): mean age 64 years; 66% male; mean baseline FEV1 1.05 l (37.7% predicted). After 12 weeks, the average post-dose FEV1 over 12 h was significantly higher with tiotropium compared with salmeterol (167 vs. 130 mL, respectively, p=0.03), as was peak FEV1 (262 vs. 216 ml, respectively, p=0.01). The average FEV1 responses from 0-6 h and 6-12 h were higher in the tiotropium group compared with salmeterol (p<0.05). Peak and average FVC were significantly higher with tiotropium compared with salmeterol (p<0.01). Morning pre-dose FEV1 responses were not significantly different; however, tiotropium demonstrated a significantly higher pre-dose FVC than salmeterol (p<0.05). CONCLUSION: Tiotropium demonstrated significantly greater post-dose improvements in spirometric parameters compared with salmeterol. These improvements were sustained over 12 h.

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.

Diffuse pneumonia and acute respiratory failure due to infectious mononucleosis in a middle-aged adult.

This report describes a 48-yr-old patient who developed bilateral hilar adenopathy, diffuse pulmonary infiltrates, and respiratory failure in association with infectious mononucleosis. Lung and paratracheal lymph node biopsies suggested the diagnosis, and an acute Epstein-Barr virus infection was confirmed serologically. Pulmonary involvement in infectious mononucleosis is reviewed, and atypical features, which may lead to diagnostic difficulty, particularly in the older adult, are discussed.

Modulation of the development of bleomycin-induced fibrosis by deferoxamine.

Bleomycin is an antineoplastic compound which produces a time- and dose-dependent pulmonary fibrosis. The mechanisms which cause this fibrosis are not known. The ability of bleomycin to produce oxygen radicals in the presence of iron and molecular oxygen appears to be related to the fibrosis. Previous studies, which have examined single time points utilizing the ferric ion chelator deferoxamine and iron-deficient diets, suggest that iron plays a central role in bleomycin-induced pulmonary fibrosis. Therefore, the present study was designed to determine the effects of deferoxamine on the development of bleomycin-induced pulmonary fibrosis. Deferoxamine pretreatment and daily injections resulted in a significant reduction in lung collagen content and lung lipid peroxidation 21 days after intratracheal bleomycin compared with bleomycin treatment alone. In addition deferoxamine treatment significantly inhibited lung DNA increases at 4, 7, and 14 days after bleomycin treatment compared with bleomycin treatment alone. These data indicate that deferoxamine treatment reduces the development of bleomycin-induced pulmonary fibrosis in the later phase. The mechanism might be by the prevention of iron-catalyzed, free-radical formation and modulation of some cellular functions.

Effect of iron deficiency on bleomycin-induced lung fibrosis in the hamster.

Bleomycin produces a dose- and time-dependent interstitial pulmonary fibrosis in humans, and is widely used to produce an animal model for the study of interstitial pulmonary fibrosis. The mechanism(s) for bleomycin-induced pulmonary fibrosis is (are) unknown, but the production of oxygen radicals by a ferrous ion-molecular oxygen pathway might be related to the fibrosis. Therefore, we studied the effect of iron deficiency on the biochemical, inflammatory, and morphologic parameters of bleomycin-induced pulmonary fibrosis in the hamster. Mild iron deficiency was induced in hamsters by bleeding via the retro-orbital sinus and maintenance on an iron-deplete diet. After intratracheal administration of bleomycin (1 U), there was no accumulation of lung collagen in the iron-deficient bleomycin-treated animals. In comparison, iron-replete animals treated with bleomycin exhibited a significant (p less than 0.01) increase in lung collagen. In addition, bleomycin-treated iron-replete animals had increased lung lipid peroxidation (p less than 0.05), whereas bleomycin-treated iron-deficient animals did not (p greater than 0.05). Lung DNA and morphometric estimates of the lesion severity were significantly increased in both iron-replete and iron-deficient bleomycin-treated animals. These data indicate that iron deficiency is associated with a reduction in the severity of bleomycin-induced pulmonary fibrosis, possibly by the prevention of iron-catalyzed oxygen-radical formation and lipid peroxidation.

Guanidine in type B botulism.

On two occasions, guanidine produced clinical and electrophysiological improvement in a 54-year-old man with botulism, type B. However, guanidine was ineffective for autonomic dysfunction. There were no intolerable side effects. Our experience showed that guanidine is also effective in botulism, type B, as adjunctive therapy.