Inhaled medicines are designed mainly to provide safe and efficacious treatment of respiratory diseases, offering the potential advantages of targeted drug delivery such as reduced onset time and increased therapeutic ratio. However, as a flipside of targeted drug delivery, drug levels in the relevant effect compartment cannot be easily assessed. In combination with technical challenges associated with aerosolizing and administering an inhaled medicine, this renders inhalation product development demanding in the regulatory aspect as well. Emerging technologies that could address some of these challenges include (i) mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modeling, which in combination with experimental techniques such as positron emission tomography could provide information on local target engagement; (ii) patient-feedback features in combination with electronic monitoring, which may improve patient adherence as well as patient handling; and (iii) controlled-release formulations and nanotechnology-based formulations with high drug load, which may expand the scope of development of compounds and targets suitable for inhalation product development.

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Embryo implantation is initiated by interaction of trophoblast with uterine epithelium via the apical cell poles of both partners. Using spheroids of human trophoblastoid JAR cells and monolayers of human uterine epithelial RL95-2 cells to simulate this initial interaction, we previously demonstrated that formation of stable cell-to-cell bonds depends on actin cytoskeleton (F-actin) and small GTPases of the Rho family, most likely RhoA. In this study, we determined the apical as well as the basal distribution of these proteins by fluorescence confocal microscopy before and after binding of JAR spheroids. We focussed on changes in cytoplasmic organization with respect to apicobasal polarity of RL95-2 cells. Before binding of spheroids, significantly higher fluorescence signals of RhoA [37 ± 6 grey scale values (gsv)] and of F-actin (41 ± 3 gsv) were found in the basal region of RL95-2 cells as compared to the apical pole (RhoA: 24 ± 3 gsv, F-actin: 28 ± 2 gsv). After binding of JAR spheroids, this apicobasal asymmetry was inverted (RhoA: 55 ± 10 gsv apical vs. 25 ± 3 gsv basal; F-actin: 108 ± 17 gsv apical vs. 57 ± 7 gsv basal). Inactivation of Rho GTPases in RL95-2 cells by Clostridium difficile toxin A leads to a loss of their apical adhesion competence, as previously published. Here, we observed a uniform distribution of RhoA and F-actin between apical and basal region rather than an asymmetric one in toxin A-treated cells. These data suggest that activation of Rho GTPases and coordinated rearrangement of F-actin within uterine epithelial cells in response to trophoblast binding are part of a generalized structural and functional reorganization of the cytoplasm. This involves not only the immediate contact zone (apical) but also the opposite (basal) cell pole and may be a critical element of uterine epithelial reactions during transition between trophoblast adhesion and transmigration.

At the time of maximum plasma concentration the additional decrease in BP relative to baseline due to the food effect will be about 7-15% for DBP and 3-9% for SBP. After administration of the 10 mg solution with a mean Cmax of 8.7 micrograms.l-1, only headache and flush with mild severity have been reported as adverse events. These maximum concentrations are comparable to Cmax values seen after intake of 40 mg NCC with food. With regard to heart rate (HR) there were distinct differences between the two formulations: Following administration of 5, 10 and 20 mg nisoldipine solution, there were dose-dependent increases in HR by a maximum of 4, 12 and 16 beats.min-1, respectively, whereas the HR profile for the NCC was similar to that seen under placebo treatment.