Farmacologisch onderzoek van Myc 1080 (stercuronium) : een nieuwe kortwerkende motorische-eindplaatremmer

Nieuwe geneesmiddelen komen vrijwel uitsluitend voort uit de researchinspanning van de farmaceutische industrie. Deze research is multi-disciplinair en indrukwekkend van omvang. De organisatie is dusdanig opgebouwd, dat een goede coordinatie van de activiteiten der diverse laboratoria wordt bereikt. Het overgrote deel van de researchactiviteiten in de farmacasector is gericht op het ene doel: de ontwikkeling van een of enkele nieuwe geneesmiddelen. Gedeeltelijk echter bestaat het onderzoek dat de verschillende wetenschappelijke medewerkers verrichten uit z. g. vrije research: men kan vrij onderzoek verrichten op gebieden, waarin men persoonlijk is geinteresseerd. Dit proefschrift is voortgekomen uit zulk een combinatie van gerichte en vrije research

Anti-GD2 Immunoliposomes for Targeted Delivery of the Survivin Inhibitor Sepantronium Bromide (YM155) to Neuroblastoma Tumor Cells

Purpose: Sepantronium bromide (YM155) is a hydrophilic quaternary compound that cannot be administered orally due to its low oral bioavailability; it is furthermore rapidly eliminated via the kidneys. The current study aims at improving the pharmacokinetic profile of YM155 by its formulation in immunoliposomes that can achieve its enhanced delivery into tumor tissue and facilitate uptake in neuroblastoma cancer cells. Methods: PEGylated YM155 loaded liposomes composed of DPPC, cholesterol and DSPE-PEG2000 were prepared via passive film-hydration and extrusion method. Targeted (i.e. immuno-)liposomes were prepared by surface functionalization with SATA modified monoclonal anti-disialoganglioside (GD2) antibodies. Liposomes were characterized based on their size, charge, antibody coupling and YM155 encapsulation efficiency, and stability. Flow cytometry analysis and confocal microscopy were performed on IMR32 and KCNR neuroblastoma cell lines. The efficacy of developed formulations were assessed by in-vitro toxicity assays. A pilot pharmacokinetic analysis was performed to assess plasma circulation and tumor accumulation profiles of the developed liposomal formulations. Results: YM155 loaded immunoliposomes had a size of 170 nm and zeta potential of −10 mV, with an antibody coupling efficiency of 60% andYM155 encapsulation efficiency of14%. Targeted and control liposomal formulations were found to have similar YM155 release rates in a release medium containing 50% serum. An in-vitro toxicity study on KCNR cells showed less toxicity for immunoliposomes as compared to free YM155. In-vivo pharmacokinetic evaluation of YM155 liposomes showed prolonged blood circulation and significantly increased half-lives of liposomal YM155 in tumor tissue, as compared to a bolus injection of free YM155. Conclusions: YM155 loaded immunoliposomes were successfully formulated and characterized, and initial in-vivo results show their potential for improving the circulation time and tumor accumulation of YM155

Anti-GD2 Immunoliposomes for Targeted Delivery of the Survivin Inhibitor Sepantronium Bromide (YM155) to Neuroblastoma Tumor Cells

Purpose: Sepantronium bromide (YM155) is a hydrophilic quaternary compound that cannot be administered orally due to its low oral bioavailability; it is furthermore rapidly eliminated via the kidneys. The current study aims at improving the pharmacokinetic profile of YM155 by its formulation in immunoliposomes that can achieve its enhanced delivery into tumor tissue and facilitate uptake in neuroblastoma cancer cells. Methods: PEGylated YM155 loaded liposomes composed of DPPC, cholesterol and DSPE-PEG2000 were prepared via passive film-hydration and extrusion method. Targeted (i.e. immuno-)liposomes were prepared by surface functionalization with SATA modified monoclonal anti-disialoganglioside (GD2) antibodies. Liposomes were characterized based on their size, charge, antibody coupling and YM155 encapsulation efficiency, and stability. Flow cytometry analysis and confocal microscopy were performed on IMR32 and KCNR neuroblastoma cell lines. The efficacy of developed formulations were assessed by in-vitro toxicity assays. A pilot pharmacokinetic analysis was performed to assess plasma circulation and tumor accumulation profiles of the developed liposomal formulations. Results: YM155 loaded immunoliposomes had a size of 170 nm and zeta potential of −10 mV, with an antibody coupling efficiency of 60% andYM155 encapsulation efficiency of14%. Targeted and control liposomal formulations were found to have similar YM155 release rates in a release medium containing 50% serum. An in-vitro toxicity study on KCNR cells showed less toxicity for immunoliposomes as compared to free YM155. In-vivo pharmacokinetic evaluation of YM155 liposomes showed prolonged blood circulation and significantly increased half-lives of liposomal YM155 in tumor tissue, as compared to a bolus injection of free YM155. Conclusions: YM155 loaded immunoliposomes were successfully formulated and characterized, and initial in-vivo results show their potential for improving the circulation time and tumor accumulation of YM155

Limits and Borders: Stages of Transboundary Water Management

Contains fulltext : 111706.pdf (publisher's version ) (Closed access)16 p

Europe’s Rhine power: connections, borders, and flows

This article explores the pivotal position of the river Rhine in the gradual development of a European electricity system. Although the general image of the Rhine is one of a inland transport corridor, it also acted as a backbone of electricity supply systems since the dawn of the 20th century. By relying on insights from both water history and history of technology, the article argues for a transnational approach to better?grasp the dynamics of river use and related electricity generation, which often went below, as well as above and beyond nation-state affairs