The pharmacokinetic and pharmacodynamic effects of inhaled corticosteroids (ICS) have shaped the efficacy and safety of these agents in the treatment of asthma.Important pharmacokinetic and pharmacodynamic characteristics that can enhance the efficacy of ICS include small particle size, high glucocorticoid-receptor-binding affinity, long pulmonary residence time and lipid conjugation. These characteristics can increase or prolong the antiinflammatory effects of an ICS. Important pharmacokinetic characteristics that can enhance the safety of ICS include on-site activation in the lung, low oropharyngeal exposure, negligible oral bioavailability, high protein-binding and rapid systemic clearance.The degree of oropharyngeal exposure is relevant to local side-effects, such as oropharyngeal candidiasis, dysphonia and coughing. Pharmacokinetic properties that influence the degree of systemic exposure are relevant to the pharmacodynamic effect of ICS-induced hypothalamicpituitary-adrenal axis suppression and cortisol suppression, an indicator of potential long-term systemic side-effects, such as reduced growth velocity and bone density, fractures, and skin bruising and thinning.Therefore, significant differences in the pharmacokinetic and pharmacodynamic characteristics of the currently available inhaled corticosteroids warrant careful consideration when used in clinical practice as they may result in differences in efficacy and local and systemic safety profiles.

The dose-proportional, intraindividual, single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor under investigation for chronic obstructive pulmonary disease and asthma, was investigated in healthy subjects. In an open, randomized, 2-period, 2-sequence crossover study, 15 subjects received immediate-release tablets of roflumilast 250 or 500 microg as single (day 1) and as repeated, once-daily doses for 8 days (days 5-12). Dose-adjusted point estimates and 90% confidence intervals of test (500 microg)/reference (250 microg) ratios for AUC and Cmax of roflumilast and its pharmacologically active N-oxide metabolite after single and repeated dosing were all within the standard equivalence acceptance range (0.80, 1.25) indicating dose proportionality. The pharmacokinetic properties of both roflumilast dosage forms provide clinically relevant evidence of predictable, intraindividual total (AUC) and maximum (Cmax) exposure of roflumilast and roflumilast N-oxide. Repeated oral dosing with roflumilast 250 and 500 microg once daily was well tolerated.

We performed a phase I/II trial in North America of a recombinant tory distress syndrome and impaired surfactant function is assosurfactant protein C-based surfactant (Venticute) as treatment for ciated with improved survival. This improvement is observed the acute respiratory distress syndrome. Patients were prospectively even in the case of established respiratory distress syndrome randomized to receive either standard therapy or standard therapy in which significant lung inflammation is present (7,8). Fourth, plus one of two doses of exogenous surfactant given four times over surfactant modifies the production by neutrophils of reactive 24 hours. Surfactant administration was well tolerated. No significant oxygen species (9) and also modulates immune responses (10). multicenter randomized trial, and no effect on survival at 30 days was demonstrated (17). be critical for optimal function and because instillation is the Acute respiratory distress syndrome (ARDS) is an acute inonly mechanism currently available for delivering adequate flammatory pulmonary injury in which marked edema of the amounts of surfactant, we studied the effects of a recombinant lungs results in progressive impairment of gas exchange, atelecsurfactant protein C (rSP-C, lusupultide)-based surfactant tasis, and decreased lung compliance. Function of the lung (Venticute; ALTANA Pharma AG, Konstanz, Germany) in surfactant system is impaired in patients with ARDS, and this an animal model of ARDS before this clinical study. We deterimpairment may contribute to atelectasis and decreased pulmomined dosage, instillation techniques, and volumes that optinary compliance (1-4). The loss of surfactant function is multimally improved gas exchange, and these preclinical observations determined and causes include injury to the type II cells of were then used to design the phase I/II study reported here the alveolar epithelium that produce surfactant components, (18,19). In addition, we chose to deliver four instillations, as inhibition caused by proteins in alveolar edema fluid, conversion prior experience with a natural surfactant did not support the of functional surfactant forms in the alveolar space to relatively use of additional doses (13). The study reported here had two inactive forms, and alteration of surfactant components by inobjectives: to assess the safety and efficacy of two dose levels flammatory processes (5).of rSP-C surfactant and to assess BAL recovered from patients Rationale for the use of exogenous surfactant in the treatfor the presence and function of surfactant components and ment of patients with ARDS rests on multiple observations (6).for evidence of treatment effect on pulmonary inflammation. First, the function of surfactant recovered in bronchoalveolar lavage fluid (BAL) from patients with ARDS and from animal METHODS models of acute lung injury is greatly impaired. Second, adminisComplete details of study methods are provided in the online supplement.tration of surfactant to animal models of ARDS results in The study was ...