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Objective To evaluate the efficacy and safety of fluticasone propionate administered as a once-daily or twice-daily regimen over a period of 1 year to patients with moderate asthma. Design Double-blind, randomized, parallel group, and placebo-controlled phase (12 weeks) and an open-label phase (54 weeks). Setting Multicenter study in an outpatient setting. Participants Patients (n = 253; age,≥ 12 years) with a mean FEV 1 of 67% predicted normal were stratified according to baseline therapy of maintenance inhaled corticosteroids vs β 2 -agonists alone. Measurements and interventions Fluticasone propionate (250μ g bid or 500 μg qd) or placebo (bid) was administered via the Diskus multidose powder inhaler (Glaxo Wellcome; Research Triangle Park, NC) for 12 weeks. During open-label treatment, patients were re-randomized to once-daily or twice-daily fluticasone propionate. Results Compared to placebo, fluticasone propionate administered qd or bid significantly improved FEV 1 (p 1 , albuterol use, and withdrawal due to lack of efficacy. During 54 weeks of open-label treatment, FEV 1 and PEF continued to improve with both regimens, and improvements seen in the first 12 weeks were maintained in patients who switched from twice-daily to once-daily dosing. Fluticasone propionate treatment over a 54-week period was well tolerated, with few drug-related adverse events, which were primarily topical effects of inhaled corticosteroids. Conclusions Fluticasone propionate powder improved lung function when administered either qd or bid over a 1-year period to patients with moderate asthma, with twice-daily dosing demonstrating significantly greater improvement in some efficacy parameters than once-daily dosing over the first 12 weeks of treatment. Fluticasone propionate treatment was not associated with significant systemic effects.

Oxygen radical release from adhering polymorphonuclear leukocytes (PMN) has been implicated as an important feature of many vascular diseases. We developed a technique by which adherence and production of O2 radicals by PMN can be measured simultaneously. The technique combines the conventional nylon fiber assay for measuring adherence of PMN with concurrent scintillation counter measurement of chemiluminescence (CL) to assess O2 radical production by PMN. We found that adherence of PMN to nylon fiber is associated with increases in CL. Moreover, increases in CL appear to be dependent on generation of O2 radicals from PMN since they are not seen with PMN from a patient with chronic granulomatous disease (CGD) or in the presence of O2 radical scavengers, superoxide dismutase, or catalase. Furthermore, agents which increase the adherence of PMN to nylon fiber are associated with increases in CL. Use of this approach may facilitate simultaneous evaluation of adherence and O2 radical generation by PMN.

O 2 radicals are important in health and disease. The most commonly used ways of identifying O 2 radicals in PMN are described above. Several shortcomings exist in these methods reflecting the unusual, complex nature of O 2 radical biochemistry. Some general principles include (1) O 2 radicals are very short-lived, reacting with many other compounds and each other quickly. (2) There are no highly specific assays for O 2 radicals. (3) Highly specific scavengers of O 2 radicals also do not exist. (4) No methods have been found to detect and quantitate O 2 radicals in vivo . (5) Solubility and membrane permeability of various scavengers and/or test reagents may affect the measurement of O 2 radicals in PMN and other biological systems. In general, the best approach to measurement of O 2 radicals involves using the best assay available and showing that the reaction is inhibited by scavengers in proportion to their reactivity with the specific O 2 radical being assayed.

Chemiluminescence was used to determine opsonic requirements for interaction of Cryptococcus neoformans with human peripheral blood polymorphonuclear leukocytes (PMNLs) and monocytes (MNs). Peak chemiluminescence (mean 1 SD) was 172 1 25 x 103 for PMNLs and 50 1 13 x 103 for MNs with 20%0 pooled normal human serum vs. 10 1 3 x 103 for PMNLs and 6 1 1 x 103 for MNs without serum (P< 0.005 for each comparison). The nature of the serum requirement was investigated; alternative pathway serum complement components were necessary. The alternative pathway was activated directly by C. neoformans without the need for specific antibody. Chemiluminescence provided a quantitative and reproducible assay of the interaction of human phagocytes with C. neoformans and may be useful in studying opsonic requirements of other fungi. Previous investigations have suggested that heatlabile opsonins- most likely complement- are needed for the effective uptake of Cryptococcus neoformans by polymorphonuclear leukocytes (PMNLs), but the techniques that were used involved morphologic slide approaches, which are very difficult to evaluate and quantitate accurately

Polymorphonuclear leukocytes (PMN) or neutrophils have multiple systems available for killing ingested bacteria. Nearly each of these incorporates H2O2 indicating the essential nature of this reactive oxygen intermediate for microbicidal activity. Following ingestion of bacteria by PMN, H2O2 is formed by the respiratory burst which consumes O2 and generates H2O2 from O2 .-. H2O2 is deposited intracellularly near bacteria within phagocytic vacuoles where it can react with the MPO-H2O2-halide system to form toxic hyperchlorous acid (HOCl) and/or possibly singlet oxygen (1O2). H2O2 can also react with O2 .- and/or iron (Fe++) from lactoferrin or bacteria to form the highly toxic hydroxyl radical (.OH). These mechanisms appear important since deficiencies of H2O2 production, myeloperoxidase or lactoferrin frequently increases their owner's susceptibility to infection. In particular, examination of PMN from infection prone patients with chronic granulomatous disease (CGD) most clearly demonstrates the importance of H2O2 in killing of bacteria. CGD PMN lack the capacity to effectively generate H2O2 and subsequently have impaired ability to kill catalase positive (H2O2 producing) but not catalase negative (not H2O2 producing) bacteria. PMN also have catalase and glutathione peroxidase systems in their cytoplasms to protect themselves from the toxicity of H2O2. Finally, while H2O2 is critical for host defense, it can also be released extracellularly and thereby play a significant role in PMN mediated tissue injury.

Addition of untreated or glutaraldehyde-fixed human erythrocytes decreased hydrogen peroxide (H2O2)-mediated acute edematous injury in isolated rat lungs, H2O2-induced damage to cultured bovine pulmonary artery endothelial cells, and H2O2-dependent oxidation of reduced cytochrome C in vitro. The results suggest that intact erythrocytes can scavenge H2O2, and as a result, protect the lung and possibly other tissues from damage.