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There is a high demand for drug delivery systems that enable local therapy of esophageal diseases such as eosinophilic esophagitis. For the development of such drug delivery systems, suitable in vitro test procedures are needed that allow a biorelevant characterization of dosage forms. With the help of the new test system presented in this thesis it is now possible to simulate the application site esophagus and to characterize the dissolution behavior of esophageal applied drug delivery systems under special consideration of physiological parameters like salivary flow rate, intensity of peristalsis, and posture of the patient. In this work, the dissolution of mucoadhesive films for esophageal application with the new device was investigated and compared to the results obtained with the compendial standard device (USP 2 apparatus). Selleckchem MAPK inhibitor The results show that the novel test system is a promising tool for the early evaluation of locally applied oral formulations for esophageal application.The development of nucleic acid drugs with unique structures and mechanisms has stimulated great research interest. Herein, we report a general strategy to construct "stapled" structures of single-stranded antisense oligonucleotides (ASONs) with a stimuli-responsive feature. "Stapled" cyclic structures can be synthesized with reactive bifunctional handles that react with thiol groups of phosphorothioate (PS)-modified ASONs, and can be alternatively adjusted depending on the desired PS sites in the ASON strand. The disulphide group in the stapled handle can be cleaved in the reducing microenvironment of tumour cells. Thus, "stapled" ASONs may be transformed back to a linear conformation to facilitate binding to target mRNAs. Stapling conferred protection against degradation, and enhanced anti-tumour activity compared to linear counterparts. This study provides a new, effective, and convenient strategy for designing ASONs with "stapled" structures, and also adds a further contribution to facilitate the stability and biological efficacy of novel nucleic acid-based therapeutics.Pain, a severe public health problem, can affect patient quality of life when inadequately controlled. Considering that pain pathophysiological mechanisms are complex, combining active pharmaceutical ingredients (APIs) with multiple and synergistic mechanisms of action represents a potentially more effective therapeutic approach than conventional monotherapy treatments. In turn, topical drug delivery has clear advantages over other routes of administration, such as high levels of efficacy, better safety profile and great patient compliance. In this context, the combination of two or more APIs in a single dosage form - fixed-dose combination product (FDC) - for topical administration may represent a promising therapeutic option in the field of pain management. Considering the above mentioned, the purpose of this manuscript is to address an overview of some general aspects regarding pain management and FDCs, as well as the regulatory environment that has to be taken into consideration during their development. Special emphasis will be given to fixed-dose combinations for topical administration with analgesic and/or anti-inflammatory activity. Market drivers of the topical FDC currently approved are ultimately pointed out, and new opportunities in pain management highlighted.Microdialysis is a pharmacokinetic tool that can be advantageous when obtaining tissues' pharmacokinetic information. Since absolute extracellular tissue concentrations are needed in pharmacokinetic studies, calibrating the microdialysis system is necessary. The internal standard method is superior when compared to other calibration methods. However, thorough evaluation of the internal standard is required before it can be used. In vitro experiments and an in vivo study on pigs (n = 8) were conducted to assess the relative recoveries by gain and by loss for piperacillin, both with and without a benzylpenicillin concentration of 5 µg/mL. Furthermore, the in vivo setup allowed for an evaluation of piperacillin cancellous bone and subcutaneous tissue concentrations in a single 8 h dosing interval. Ultra-high performance liquid chromatography (UHPLC) was used to determine piperacillin and benzylpenicillin concentrations. Relative recovery by loss for benzylpenicillin and relative recovery by gain for piperacillin were similar in in vitro and in vivo. Presence of benzylpenicillin did not affect the relative recovery for piperacillin. Relative recovery, pharmacokinetic parameters and fT>MIC were similar when comparing the retrodialysis by drug and the internal standard calibration methods (p > 0.31). Mean fT>MIC (16 µg/mL) for plasma, cancellous bone and subcutaneous tissue were 232 min, 255 min and 295 min, respectively. Our findings suggest that benzylpenicillin is suitable as an internal standard for piperacillin in microdialysis studies. Mean fT>MIC (16 µg/mL) for plasma, cancellous bone, and subcutaneous tissue reached a target of 50% fT>MIC under the investigated conditions (mean range 52%-66%); however, the target was not obtained in all pigs in all compartments. Moreover, 100% fT>MIC was not obtained in any case, suggesting that different strategies must be taken into consideration if higher targets are employed.We study the influence of population heterogeneity on herd immunity level and on individual's vaccination decision making process. We first formulate the mathematical model in a population with two subgroups, based on different activity levels or different susceptibilities. The herd immunity threshold is derived and discussed. It is calculated that the required vaccine coverage level for herd immunity in a heterogeneous mixing population can be varied significantly. The required vaccine coverage level is lower than the classical herd immunity level, if the vaccine coverage level in the more active group or more susceptible group is higher than the other subgroup. It is suggested that the classical herd immunity levels can be misleading in the process of planning mass vaccination programs. The analysis is further extended to study the population with more subgroups. We then study the formal vaccination games to simulate the process of vaccination decision making, in either homogeneous or heterogeneous mixing populations.
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