Yes / Background Chronic infections with Pseudomonas aeruginosa are a leading cause of morbidity in patients with cystic fibrosis (CF). Tobramycin nebulizer solution (TNS) is indicated for maintenance therapy in CF patients. TOBI® is a tobramycin nebulizer solution (TNS) approved by FDA for maintenance therapy for patient with CF. Adherence to recommended therapy in CF has always been a challenge and new generation nebulizers are increasingly used “off label” to reduce the time required for inhalation, potentially improving patient compliance. Objectives To assess the performance of selected recent nebulizer delivery systems for determination the optimum combinations to deliver TOBI®. Using the relative lung bioavailability of TOBI® to the lungs in healthy volunteers, following inhalation from selected nebulizer delivery systems, using a urinary pharmacokinetics method. In vitro aerodynamic characteristics of the nebulized dose were also determined. Methods Serial urine samples were collected from 12 healthy volunteers up to 24 h post-inhalation of TOBI® inhaled solution following delivery by Pari LC Plus®, Sidestream®, NE-U22-E Omron® and Aeroneb® Go nebulizers. In vitro aerodynamic characteristics of the nebulized dose were also determined according to the CEN (Committee European de Normalization) method. Results The mean (SD) relative lung bioavailability from Pari LC Plus®, Sidestream®, Omron®, and Aeroneb® Go nebulizers was 4.9 (0.5), 3.9 (0.5), 7.1 (1.3), and 7.7 (0.7) %, respectively. The mean (SD) mass median aerodynamic diameter (MMAD) of the drug particles from the same systems was 2 (0.2), 2 (0.2), 1.2 (0.03) and 2.0 (0.1) μm, and the corresponding fine particle doses (FPD) were 2.2 (0.23), 1.5 (0.2), 3.44 (0.3) and 2.8 (0.3) mg. Conclusion The data obtained from in-vitro and in-vivo studies reflect poor relative lung bioavailability of tobramycin following jet nebulization.

The thesis deals with the determination of fracture toughness using compact tension (CT) test specimens at elevated and high temperatures. The experimental material steel P91 designated for application at temperatures 550650°C was used. The fracture toughness in the ductile fracture region of the steel was characterized by the R curve, which characterises the resistance against crack propagation depending on the crack length. The effect of temperature on the R curve at range 23600°C was evaluated. Next the specimen size effect using three sizes of CT specimens at 23°C and the effect of loading rate (2, 0,2 a 0,02 mm/min) at 600°C was examined. The results showed that the temperature has distinct effect on the R-curve, which yields minimal values at 400°C. Only the smallest test specimen size with thickness 6.25mm showed the specimen size effect giving about 10% lower values of toughness comparing to larger specimens. The effect of loading rate was clearly distinguishable. The values of toughness varied about 20% of the toughness value comparing individual loading rate.