Utrecht, Netherlands
Utrecht, Netherlands

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Lilih S.,Pharmacy Foundation of Haarlem Hospitals | Lilih S.,Universiteitsweg 99 | Pereboom M.,Pharmacy Foundation of Haarlem Hospitals | van der Hoeven R.T.M.,Pharmacy Foundation of Haarlem Hospitals | And 2 more authors.
International Journal of Medical Informatics | Year: 2017

Objective Gastrointestinal bleedings are the most frequently occurring reason for medication-related hospital admissions, which are potentially preventable. We implemented a clinical decision support system that recommends to prescribe gastrointestinal prophylaxis in patients with an increased risk according to the Dutch guideline. Our primary objective was to determine whether the implementation resulted in improved compliance with this guideline for gastrointestinal prophylaxis. A secondary objective was to determine whether implementation resulted in a reduction of the number of drug safety alerts. Materials and methods This intervention study was performed at the Spaarne Gasthuis, a teaching hospital, using Epic as hospital information system. We selected prescriptions with an indication for gastrointestinal prophylaxis according to the guideline, in the three months before and after implementation of the clinical decision support in November 2014. We analyzed whether gastrointestinal prophylaxis was prescribed more frequently after implementation using the Pearson's Chi-square test and the change in the number of drug safety alerts. Results Before implementation in 84.0% of the included 2064 prescriptions gastrointestinal prophylaxis was co-prescribed. After implementation this percentage increased to 94.5% of the 2269 prescriptions (p < 0.001). The number of drug safety alerts decreased by 78.2% from 980 to 217 alerts. Conclusion The introduction of a clinical decision support system for gastrointestinal prophylaxis improved adherence to the Dutch guideline. This was most likely due to a reduction in the number of irrelevant drug safety alerts. © 2016 Elsevier Ireland Ltd


Wieczorek B.,Universiteitsweg 99 | Wieczorek B.,Novo Nordisk AS | Snelders D.J.M.,Universiteitsweg 99 | Dijkstra H.P.,Universiteitsweg 99 | And 6 more authors.
Organometallics | Year: 2012

The coordination chemistry in aqueous media was studied for the platinum center of low-molecular-weight cationic NCN-pincer platinum complexes [RC 6H 2(CH 2NMe 2) 2-3,5- Pt(H 2O)-4] + (R = -(CH 2) 3P(=O)(OEt) (OC 6H 4NO 2-4) (1(OH 2)), H (2(OH 2))) as well as of the platinum center of the NCN-pincer platinum cation embedded in the lipase cutinase (cut-1; molecular weight 20 619.3) with various anionic, neutral, and cationic triarylphosphines. A 31P NMR study of the coordination of triarylphosphines to the cationic NCN-pincer platinum center in low-molecular-weight [2(OH 2)][OTf] in both D 2O and Tris buffer (Tris = tris(hydroxylmethyl)aminomethane) showed that the phosphine-platinum coordination is strongly affected by Tris buffer molecules. Two crystal structures of a NCN-pincer platinum-phosphine and a NCN-pincer platinum-ethanolamine coordination complex with ethanolamine as a functional model of Tris with hydrogen bridges, provoking a dimeric supramolecular structure, confirmed that the coordination observed in solution occurred in the solid state as well. A 31P NMR and ESI-MS study of the lipase cut-1 showed that the coordination of various triarylphosphines to the enzyme-embedded platinum center is affected by the surrounding protein backbone, discriminating between phosphines on the basis of their size and charge. By using 31P NMR spectroscopy and ESI-MS spectrometry, study of the coordination of triarylphosphines to cut-1 was possible, thereby avoiding the need for the application of laborious biochemical procedures. To the best of our knowledge, this is the first example of a study involving the selective binding of organic ligands to the metal center of a semisynthetic metalloprotein, unequivocally demonstrating that the well-established coordination chemistry for small-molecule complexes can be transferred to biological molecules. This initial study allows future explorations in the field of selective protein targeting and identification, as in protein profiling or screening studies. © 2012 American Chemical Society.


Fong H.,California Institute of Technology | Moret M.-E.,California Institute of Technology | Moret M.-E.,Universiteitsweg 99 | Lee Y.,California Institute of Technology | And 2 more authors.
Organometallics | Year: 2013

Reversible, heterolytic addition of H2 across an iron-boron bond in a ferraboratrane with formal hydride transfer to the boron gives iron-borohydrido-hydride complexes. These compounds catalyze the hydrogenation of alkenes and alkynes to the respective alkanes. Notably, the boron is capable of acting as a shuttle for hydride transfer to substrates. The results are interesting in the context of heterolytic substrate addition across metal-boron bonds in metallaboratranes and related systems, as well as metal-ligand bifunctional catalysis. © 2013 American Chemical Society.


Kroon J.,Leiden University | Kroon J.,University of Twente | Metselaar J.M.,University of Twente | Metselaar J.M.,MIRA Institute for Biological Technology and Technical Medicine | And 5 more authors.
Cancer Treatment Reviews | Year: 2014

Prostate cancer is the most common cancer type and the second leading cause of death from cancer in males. In most cases, no curative treatment options are available for metastatic castration-resistant prostate cancer as these tumors are highly resistant to chemotherapy. Targeted drug delivery, using liposomal drug delivery systems, is an attractive approach to enhance the efficacy of anticancer drugs and prevent side effects, thereby potentially increasing the therapeutic index. In most preclinical prostate cancer studies, passive liposomal targeting of anticancer drugs (caused by enhanced permeability and retention of the therapeutic compound) leads to an increased antitumor efficacy and decreased side effects compared to non-targeted drugs. As a result, the total effective dose of anticancer drugs can be substantially decreased. Active (ligand-mediated) liposomal targeting of tumor cells and/or tumor-associated stromal cells display beneficial effects, but only limited preclinical studies were reported. To date, clinical studies in prostate carcinoma have been performed with liposomal doxorubicin only. These studies showed that long-circulating, PEGylated, liposomal doxorubicin generally outperforms conventional short-circulating liposomal doxorubicin, stressing the importance of passive tumor targeting for this drug in prostate carcinoma. In this review, we provide an overview of the (pre)clinical studies that focus on liposomal drug delivery in prostate carcinoma. © 2013 Elsevier Ltd.


Hayen S.M.,University Utrecht | Hayen S.M.,Universiteitsweg 99 | Kostadinova A.I.,Universiteitsweg 99 | Kostadinova A.I.,Nutricia Research B.V. | And 4 more authors.
Current Opinion in Allergy and Clinical Immunology | Year: 2014

Combining SIT using (adapted) allergens or tolerogenic peptides with adjunct therapy may be essential to improve safety and/or efficacy. Beyond using targeted approaches, specific dietary components may be explored to reduce side-effects and support clinical tolerance induction by SIT. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Huis In 'T Veld R.,Universiteitsweg 99 | Huis In 'T Veld R.,University Utrecht | Storm G.,Universiteitsweg 99 | Hennink W.E.,Universiteitsweg 99 | And 3 more authors.
Nanoscale | Year: 2011

Macromolecular carrier materials based on N-(2-hydroxypropyl)methacrylamide (HPMA) are prototypic and well-characterized drug delivery systems that have been extensively evaluated in the past two decades, both at the preclinical and at the clinical level. Using several different imaging agents and techniques, HPMA copolymers have been shown to circulate for prolonged periods of time, and to accumulate in tumors both effectively and selectively by means of the Enhanced Permeability and Retention (EPR) effect. Because of this, HPMA-based macromolecular nanotheranostics, i.e. formulations containing both drug and imaging agents within a single formulation, have been shown to be highly effective in inducing tumor growth inhibition in animal models. In patients, however, as essentially all other tumor-targeted nanomedicines, they are generally only able to improve the therapeutic index of the attached active agent by lowering its toxicity, and they fail to improve the efficacy of the intervention. Bearing this in mind, we have recently reasoned that because of their biocompatibility and their beneficial biodistribution, nanomedicine formulations might be highly suitable systems for combination therapies. In the present manuscript, we briefly summarize several exemplary efforts undertaken in this regard in our labs in the past couple of years, and we show that long-circulating and passively tumor-targeted macromolecular nanotheranostics can be used to improve the efficacy of radiochemotherapy and of chemotherapy combinations. © 2011 The Royal Society of Chemistry.


Vader P.,University Utrecht | Vader P.,Universiteitsweg 99 | Van Der Aa L.J.,University of Twente | Engbersen J.F.J.,University of Twente | And 2 more authors.
Pharmaceutical Research | Year: 2012

Purpose: Use of RNA interference as novel therapeutic strategy is hampered by inefficient delivery of its mediator, siRNA, to target cells. Cationic polymers have been thoroughly investigated for this purpose but often display unfavorable characteristics for systemic administration, such as interactions with serum and/or toxicity. Methods: We report the synthesis of a new PEGylated polymer based on biodegradable poly(amido amine)s with disulfide linkages in the backbone. Various amounts of PEGylated polymers were mixed with their unPEGylated counterparts prior to polyplex formation to alter PEG content in the final complex. Results: PEGylation effectively decreased polyplex surface charge, salt- or serum-induced aggregation and interaction with erythrocytes. Increasing amount of PEG in formulation also reduced its stability against heparin displacement, cellular uptake and subsequent silencing efficiency. Yet, for polyplexes with high PEG content, significant gene silencing efficacy was found, which was combined with almost no toxicity. Conclusions: PEGylated poly(amido amine)s are promising carriers for systemic siRNA delivery in vivo. © The Author(s) 2011.


Yousefi A.,Universiteitsweg 99 | Storm G.,Universiteitsweg 99 | Schiffelers R.,University Utrecht | Mastrobattista E.,Universiteitsweg 99
Journal of Controlled Release | Year: 2013

Delivery of nucleic acids to tumors has received extensive attention in the past few decades since these molecules are capable of treating disease by modulating the source of abnormalities. Although high efficiency and low toxicity of numerous delivery systems for nucleic acids have been approved frequently with in vitro assays, contradictions have been observed in many cases between these results and what has occurred in the dynamic in vivo situation. Filling this gap seems to be crucial for further preclinical development of such systems. In this paper, we discuss various barriers which polymeric DNA or siRNA nanoparticles encounter upon systemic administration with an aim to assist in designing more relevant in vitro assays. Furthermore, individual considerations concerning delivery of DNA and siRNA have been addressed. © 2013 Published by Elsevier B.V.


De Mol N.J.,Universiteitsweg 99 | Kruijtzer J.A.W.,Universiteitsweg 99 | Moret E.E.,Universiteitsweg 99 | Broutin I.,University of Paris Descartes | Liskamp R.M.J.,Universiteitsweg 99
Biochimica et Biophysica Acta - Proteins and Proteomics | Year: 2013

The Grb2 adapter protein is involved in the activation of the Ras signaling pathway. It recruits the Sos protein by binding of its two SH3 domains to Sos polyproline sequences. We observed that the binding of Grb2 to a bivalent ligand, containing two Sos-derived polyproline-sequences immobilized on a SPR sensor, shows unusual kinetic behavior. SPR-kinetic analysis and supporting data from other techniques show major contributions of an intermolecular bivalent binding mode. Each of the two Grb2 SH3 domains binds to one polyproline-sequence of two different ligand molecules, facilitating binding of a second Grb2 molecule to the two remaining free polyproline binding sites. A molecular model based on the X-ray structure of the Grb2 dimer shows that Grb2 is flexible enough to allow this binding mode. The results fit with a role of Grb2 in protein aggregation, achieving specificity by multivalent interactions, despite the relatively low affinity of single SH3 interactions. © 2012 Elsevier B.V.


Bartneck M.,RWTH Aachen | Scheyda K.M.,RWTH Aachen | Warzecha K.T.,RWTH Aachen | Rizzo L.Y.,RWTH Aachen | And 9 more authors.
Biomaterials | Year: 2015

Liposomes are routinely used carrier materials for delivering drug molecules to pathological sites. Besides in tumors and inflammatory sites, liposomes also strongly accumulate in liver and spleen. The potential of using liposomes to treat acute and chronic liver disorders, however, has not yet been evaluated. We here explored the therapeutic potential of dexamethasone (Dex)-loaded liposomes for inflammatory liver diseases, using experimental models of acute and chronic liver injury in mice. Fluorescently labeled liposomes predominantly accumulated in hepatic phagocytes, but also in T cells. Importantly, Dex-loaded liposomes reduced T cells in blood and liver, more effectively than free Dex, and endorsed the anti-inflammatory polarization of hepatic macrophages. In experimental chronic liver damage, Dex-loaded liposomes significantly reduced liver injury and liver fibrosis. In immune-mediated acute hepatitis Dex-loaded liposomes, but not free Dex, significantly reduced disease severity. T cells, not macrophages, were significantly depleted by Dex liposomes in liver disease models invivo, as further supported by mechanistic cell death invitro studies. Our data indicate that Dex liposomes may be an interesting treatment option for liver diseases, in particular for immune-mediated hepatitis. The depletion of T cells might represent the major mechanism of action of Dex liposomes, rather than their macrophage-polarizing activities. © 2014 Elsevier Ltd.

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