A Search for subgroups of patients with ARDS who may benefit from surfactant replacement therapy: a pooled analysis of five studies with recombinant surfactant protein-C surfactant (Venticute).

BACKGROUND: Studies to date have shown no survival benefit for the use of exogenous surfactant to treat patients with the ARDS. To identify specific patient subgroups for future study, we performed an exploratory post hoc analysis of clinical trials of recombinant surfactant protein-C (rSP-C) surfactant (Venticute; Nycomed GmbH; Konstanz, Germany). METHODS: We performed a pooled analysis of all five multicenter studies in which patients with ARDS due to various predisposing events were treated with rSP-C surfactant. Patients received either usual care (n = 266) or usual care plus up to four intratracheal doses (50 mg/kg) of rSP-C surfactant (n = 266). Factors influencing the study end points were analyzed using descriptive statistics, analysis of covariance, and logistic regression models. RESULTS: ARDS was most often associated with pneumonia or aspiration, sepsis, and trauma or surgery. For the overall patient population, treatment with rSP-C surfactant significantly improved oxygenation (p = 0.002) but had no effect on mortality (32.6%). Multivariate analysis showed age and acute physiology and chronic health evaluation (APACHE) II score to be the strongest predictors of mortality. In the subgroup of patients with severe ARDS due to pneumonia or aspiration, surfactant treatment was associated with markedly improved oxygenation (p = 0.0008) and improved survival (p = 0.018). CONCLUSIONS: rSP-C surfactant improved oxygenation in patients with ARDS irrespective of the predisposition. Post hoc evidence of reduced mortality associated with surfactant treatment was obtained in patients with severe respiratory insufficiency due to pneumonia or aspiration. Those patients are the focus of a current randomized, blinded, clinical trial with rSP-C surfactant.

Dose-proportional intraindividual single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor.

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.

Two-dimensional and three-dimensional imaging show ciclesonide has high lung deposition and peripheral distribution: a nonrandomized study in healthy volunteers.

Drug deposition is an important factor that contributes to safety and efficacy outcomes of inhaled steroid therapy. Ciclesonide is a nonhalogenated, inhaled corticosteroid under investigation for the treatment of asthma. Therefore, this study was performed to assess lung deposition of ciclesonide. Technetium-99m (99mTc)-labeled ciclesonide (where the 99mTc-label is physically dissolved in the ciclesonide-hydrofluoroalkane [HFA] solution aerosol) inhaled by healthy volunteers was analyzed by two-dimensional (2-D) and three-dimensional (3-D) imaging to determine lung deposition. Six healthy volunteers inhaled one puff of 40 microg (exactuator, equivalent to 50 microg ex-valve) ciclesonide for 2-D imaging, and two healthy volunteers inhaled 10 puffs of 40 microg ciclesonide for 2-D and 3-D imaging. The ciclesonide aerosol was administered via metered-dose inhaler (MDI) containing HFA-134a as propellant. The ex-actuator mean (+/- standard deviation) deposition of ciclesonide in the lungs was higher (52% +/- 11%) than in the mouth/pharynx (38% +/- 14%). Two-dimensional and 3-D imaging showed that ciclesonide reached all regions of the lung. Mean percent deposition in peripheral regions (47% and 34%) was higher than in lower central regions (17% and 30%), as revealed by 3-D and 2-D imaging, respectively. Inhalation of up to 400 microg of ciclesonide produced no drug-related side effects. In conclusion, ciclesonide administered via metered-dose inhaler using HFA-134a as a propellant provided high lung deposition (>50%), greater distribution throughout peripheral regions of the lungs, and relatively low oropharyngeal deposition.

Circadian rhythm of serum cortisol after repeated inhalation of the new topical steroid ciclesonide.

UNLABELLED: The new inhalative glucocorticoid ciclesonide which is activated in lung to a more potent metabolite was hypothesized to have low risk for systemic and local side-effects in man. Therefore, a placebo-controlled, randomized, double-blind, four-period, change-over equivalence study in 12 healthy male volunteers (age 21-28 yr, body weight 62-90 kg) was conducted to assess the influence of three dosage regimens (800 microg in the morning, 800 microg in the evening, 400 microg twice daily for 7 d, metered inhalers) on the circadian time serum cortisol rhythm. RESULTS: Serum cortisol showed the typical circadian rhythm. The geometric mean of the 24-h mesor (AUC((0-24 h))/24 h) was 7.22 microg/dl for placebo, 6.75 microg/dl for the 800 microg ciclesonide morning dose, 7.08 microg/dl for the 800 microg evening dose, and 6.75 microg/dl for 400 microg ciclesonide inhaled twice daily. Because there was also no influence on cortisol amplitude and acrophase (time of maximum), the profiles after ciclesonide were equivalent to the placebo control. The small differences were considered not to be of clinical significance. In conclusion, inhaled ciclesonide in daily doses of 800 microg for 7 d is without clinically relevant effects on the hypothalamic-pituitary-adrenal axis independent of the time of administration.

The new phosphodiesterase 4 inhibitor roflumilast is efficacious in exercise-induced asthma and leads to suppression of LPS-stimulated TNF-alpha ex vivo.

Roflumilast is a new phosphodiesterase 4 (PDE4) inhibitor developed by Byk Gulden Pharmaceuticals for the treatment of chronic obstructive pulmonary disease and asthma. A placebo-controlled, randomized, double-blind, two-period crossover study was performed to investigate the safety and efficacy of roflumilast in 16 patients with exercise-induced asthma. The patients received placebo or roflumilast (500 microg/day) for 28 days, each according to the randomly determined treatment sequences roflumilast/placebo and placebo/roflumilast. In both study periods, exercise challenge was performed 1 hour after dosing on days 1, 14, and 28. FEV1 was measured before exercise challenge, immediately after the end of exercise challenge, and then at 1, 3, 5, 7, 9, and 12 minutes after the end of challenge. Blood samples for the determination of lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNF-alpha) in whole blood ex vivo as a surrogate marker for the inhibition of inflammatory cell activation were taken predose on days 1 and 28. Serial safety measurements were performed during both study periods. Analysis of variance for the crossover design showed a significant superiority of roflumilast over placebo on day 28. The mean percentage fall of FEV1 after exercise was reduced by 41% as compared to placebo (p = 0.021). An improvement of lung function during roflumilast treatment was also observed on days 1 and 14. The median TNF-alpha level decreased by 21% (p = 0.009) during roflumilast treatment but remained essentially constant under placebo. It is concluded that roflumilast is effective in the treatment of exercise-induced asthma. This result was accompanied by a significant reduction of TNF-alpha levels ex vivo. Treatment with roflumilast was safe and well tolerated.

Intragastric pH during continuous infusion with pantoprazole in patients with bleeding peptic ulcer.

OBJECTIVES: In managing patients with bleeding peptic ulcers, prevention of rebleeding is a particular challenge to hemostasis and fibrinolysis, both of which involve reactions that are impaired in acidic gastric environment. Therefore, such patients are expected to benefit from profound acid suppression. The present investigation aimed to establish a safe and, with regard to pH elevation, effective treatment that, based on in vitro evidence, should provide clinical benefit in this patient population. METHODS: Patients with acute bleeding peptic ulcers (Forrest Ia, Ib, IIa) after successful endoscopic hemostasis were enrolled in two pilot studies (N = 20 each). They were given an intravenous bolus injection of 80 mg of pantoprazole immediately followed by continuous infusion of either 6 mg/h or 8 mg/h pantoprazole for 72 h. Intragastric pH was measured continuously over 24 h and, if possible, for up to 48 h. RESULTS: Intragastric pH increased rapidly to values of about 6 with both treatments. For the 0-24 h period, the median pH values were 6.1 (68% range 4.5-7.4) and 6.1 (68% range 5.2-6.7) in patients receiving 6 mg/h and 8 mg/h continuous infusion, respectively; the values for the 0-48 h period were 5.9 (4.9-6.7) and 6.3 (5.5-7.0), respectively. The median percentage time that pH was > or =6 during the 0-48 h interval was 47% (68% range 28-89) for the 6 mg/h treatment group and 64% (68% range 41-84) for the 8 mg/h treatment group. Both treatment regimens with pantoprazole were well tolerated based on electrocardiographic measurements, vital signs, clinical laboratory values, and adverse events. CONCLUSIONS: Compared with the infusion with 6 mg/h pantoprazole, the continuous infusion of 8 mg/h pantoprazole showed a lower interindividual variability of the intragastric pH and a greater percentage of time that pH was >/ or =6. Thus, with regard to safety and efficacy, an initial 80-mg bolus injection, followed by 8 mg/h continuous infusion, seems to be the adequate treatment in patients with a high risk of rebleeding.

Treatment of acute respiratory distress syndrome with recombinant surfactant protein C surfactant.

We performed a phase I/II trial in North America of a recombinant surfactant protein C-based surfactant (Venticute) as treatment for the acute respiratory distress syndrome. Patients were prospectively randomized to receive either standard therapy or standard therapy plus one of two doses of exogenous surfactant given four times over 24 hours. Surfactant administration was well tolerated. No significant treatment benefit was associated with surfactant treatment. Bronchoalveolar lavage of treated patients at 48 hours reflected the presence of exogenous surfactant components, did not show evidence of improved surface tension lowering function, and had interleukin-6 concentrations that were significantly lower than control group values, consistent with an antiinflammatory treatment effect. The presence of exogenous surfactant was not detected in lavage fluid obtained at 120 hours. Future studies might rationally employ larger surfactant doses and a more prolonged dosing schedule.