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Inleiding Een aanzienlijk aantal militaire leerling-vliegers krijgt in de loop van de opleiding last van bewegingsziekte tijdens trainingsvluchten. Voor een aantal leerlingen is het probleem zo ernstig, dat zij een desensitisatiebehandeling moeten ondergaan. Wanneer het zou lukken de symptomen m.b.v. anti-bewegingsziektemiddelen te reduceren, zouden 1) mogelijk meer leerlingen door gewenning tijdens de vlieglessen van dit probleem kunnen afkomen en 2) zou mogelijk het rendement van een desensitisatiebehandeling verhoogd kunnen worden. Dit onderzoek heeft als doel middelen te selecteren, die 1) het meest effectief zijn tegen bewegingsziekte van leerling-vliegers tijdens vlieglessen, waarbij een goede vliegprestatie gewaarborgd moet zijn en 2) middelen te selecteren, die het meest effectief zijn om gebruikt te worden tijdens een desensitisatiebehandeling, teneinde het resultaat daarvan te optimaliseren. Methode Analyse van de relevante literatuur over de beschikbare farmacologische en alternatieve middelen, beschikbaar in de Medline-, TNO- en NASAdatabases. Resultaten en conclusies Voor gebruik door actieve leerling-vliegers komen géén van de historisch aanbevolen geneesmiddelen in aanmerking, omdat ze bijwerkingen kunnen hebben die kunnen interfereren met de optimale uitvoering van vliegtaken. Een aantal van deze middelen kan echter wel gebruikt worden om het resultaat te verbeteren van desensitisatie. Daarbij is het optreden van bijwerkingen minder kritisch. Voor dit doel is 0.3 mg scopolamine waarschijnlijk het meest geschikt. Daarbij zou tijdens de behandeling deze medicatie langzaam afgebouwd moeten worden om een terugval tegen te gaan. Toekomstig onderzoek zal moeten uitwijzen of door toediening van scopolamine de habituatie aan de bewegingsziektestimuli inderdaad versneld wordt en of er geen terugval optreedt na het staken van de medicatie. M.b.t. alternatieve middelen, concluderen we dat 1-2 g gemberpoeder en acupressuur/electrostimulatie op punt P6 mogelijk aantrekkelijke alternatieven zijn voor actieve leerling-vliegers, maar dat er nog onderzoek verricht moet worden om de effectiviteit bij bewegingsziekte afdoende aan te tonen. Mogelijk komen ook de tweede-generatie antihistaminica, zoals loratadine en fexofenadine voor deze groep in aanmerking, doch daarvoor moet eerst de effectiviteit van deze middelen bij bewegingsziekte worden onderzocht.

Sinds begin jaren tachtig gebruikt de burgerluchtvaart speurhonden voor de opsporing van verboden stoffen, zoals drugs en explosieven. Ondanks de goede reputatie van de speurhond werd nooit een groot internationaal en onafhankelijk onderzoek uitgevoerd. Samen met internationale partners deed TNO – als afsluitend onderdeel van een Europees project – proeven op luchthaven Schiphol.

Cafeïne 400mg werkt beter dan 200mg modafinil bij het acuut tegengaan van de sedatieve werking van temazepam

This paper analyses the implications of a new form of surveillance—sewage monitoring—for criminal procedural law. Current law has not been written with a view to covering novel, technology-enabled forms of covert data acquisition, posing a challenge of regulatory connection. To what extent are new surveillance methods, such as sewage monitoring to combat drugs production, covered by existing legal frameworks? This question is answered through analysing the shifting nature of criminal investigation, reflecting on how to interpret laws not written for new technologies, and assessing checks and balances needed when law enforcement employ sewage monitoring in criminal investigation. The analysis is illustrated with reference to the legal systems of Germany, Poland, and the Netherlands, using legal doctrinal research. The main findings are 1) that sewage monitoring is not particularly intrusive as such, but constitutes a new form of investigation that legally differs significantly from traditional surveillance powers, 2) that comparable methods do not provide unequivocal analogies that could serve to find a legal basis, 3) that functionality of evidence collection poses legal and procedural challenges, which may have implications for the covertness of the method, and 4) that even if only used as a diagnostic tool, some form of transparency and oversight will be needed to legitimate the non-negligible potential interference with fundamental rights and to enable those subjected to sewage monitoring to contest the usage in court.

Atherogenic lipids and chronic inflammation drive the development of cardiovascular disorders such as atherosclerosis. Many cardiovascular drugs target the liver which is involved in the formation of lipid and inflammatory risk factors. With robust systems biology tools and comprehensive bioinformatical packages becoming available and affordable, the effect of novel treatment strategies can be analyzed more comprehensively and with higher sensitivity. For example, beneficial as well as adverse effects of drugs can already be detected on the gene and metabolite level, and prior to their macroscopic manifestation. This chapter describes a systems approach for a prototype CV drug with established beneficial and adverse effects. All relevant steps, for example, experimental design, tissue collection and high quality RNA preparation, bioinformatical analysis of functional processes, and pathways (targeted and untargeted) are addressed. © 2010 Springer Science+Business Media, LLC.

Dyslipidemia and inflammation are well known causal risk factors the development of atherosclerosis. The interplay between lipid metabolism and inflammation at multiple levels in metabolic active tissues may exacerbate the development of atherosclerosis, and will be discussed in this review. Cholesterol, fatty acids and modified lipids can directly activate inflammatory pathways. In addition, circulating (modified) lipoproteins modulate the activity of leukocytes. Vice versa, proinflammatory signaling (i.e. cytokines) in pre-clinical models directly affects lipid metabolism. Whereas the main lipid-lowering drugs all have potent anti-inflammatory actions, the lipid-modulating actions of anti-inflammatory agents appear to be less straightforward. The latter have mainly been evaluated in pre-clinical models and in patients with chronic inflammatory diseases, which will be discussed. The clinical trials that are currently conducted to evaluate the efficacy of anti-inflammatory agents in the treatment of cardiovascular diseases may additionally reveal potential (beneficial) effects of these therapeutics on lipid metabolism in the general population at risk for CVD. © 2013 Elsevier Ireland Ltd.

Over the past five years, the pharmaceutical supply chain has grown increasingly unreliable. According to the US Food and Drug Administration (FDA), the figure of drug shortages has tripled between 2006 and 2010 (see Figure 1 and Figure 21). In 2010 alone 211 cases were recorded, while in 2011 up to 89 cases were recorded as early as March.2 These shortages range from cancer medication to antibiotics, anesthetics, painkillers, anti-depressants and emergency care drugs. Shortages have grave implications for the provision of healthcare, with hospitals not able to provide the right care causing patients to become ill or even perish. Drug scarcity has also been experienced in Europe where reports have surfaced of shortages in cytarabine, a leukemia drug, Thyrogen, used to treat thyroid cancer, and in Cerezyme and Fabrazyme, essential for the treatment of enzyme deficiency disorders.3 The rise of drug shortages has raised concerns among health care providers and requires effective monitoring by national authorities with possible intervention. Increasing scarcity of medication is a worrying trend, which is likely to continue for the coming decades.

TNO’s intestinal screening model (TNO i-screen) helps to quickly identify pharmacological compounds that are metabolized by intestinal microbiota. For pharmaceutical companies, searching for novel pharmaceuticals is a complex and time-consuming process. When a novel drug has been selected, extensive in vitro and clinical studies are required to demonstrate its metabolism, safety and efficacy prior to releasing it to the market. Increasing evidence has shown that gut microbiota are involved in the metabolic transformation of many drugs, influencing drug pharmacokinetics and thus, efficacy and safety profiles.

The mammalian gastrointestinal tract (GIT) harbors microorganisms (the microbiota) of vast phylogentic, genomic, and metabolic diversity, and recent years have seen a rapid development in the techniques for studying these complex microbial ecosystems. It is increasingly apparent that the GIT microbiota plays an intricate role in host health and disease. Targeted strategies for modulating human health through the modification of the GIT microbiota, however, are developing and in their infancy. This perspective article discusses the rationale, benefits and limitations of using the GIT microbiota as a pharmacological and nutritional target in the treatment of various diseases and disorders linked to imbalances in our microbiota. © 2012 Elsevier Ltd.

Nucleoside reverse transcriptase inhibitors (NRTIs) are a key class of drugs for the treatment of HIV infection. NRTIs are intracellularly phosphorylated to their active triphosphate metabolites and compete with endogenous deoxynucleotides (dNTP) for substrate binding. It is therefore important to analyze the intracellular concentrations of these compounds to understand drug efficacy and toxicity. To that purpose an analytical platform was developed that is capable of analyzing 8 NRTIs, 12 phosphorylated NRTIs and 4 dNTPs in small numbers of peripheral blood mononuclear cells, i.e. 1×106 cells. The platform consists of two liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods: a reversed-phase method for NRTIs using positive electrospray ionization (ESI) and an ion-pair LC-MS/MS method for the phosphorylated compounds using negative ESI. The methods use the same LC-MS system and column and changing from one method to the other only includes changing the mobile phase. The methods were partially validated, focussing on sensitivity, accuracy and precision. Successful transfer of the methods to ultra performance liquid chromatography (UPLC) led to a significant improvement of speed for the analysis of NRTIs and sensitivity for both NRTIs and phosphorylated NRTIs. The latter was demonstrated by the improved separation by UHPLC of dGTP vs. AZT-TP and ATP which made direct analysis of dGTP possible using the optimal MS/MS transition thereby significantly improving the detection limit of dGTP. Typically LLOQs observed for both the NRTIs and phosphorylated NRTIs were 1nM, while the mean accuracy varied between 82 and 120% and inter- and intra-assay precision was generally <20%. © 2011 Elsevier B.V.

Several studies showed that oncology nurses are exposed to antineoplastic drugs via the skin during daily activities. Several antineoplastic drugs (including cyclophosphamide) have been classified as carcinogenic to humans. This study aims to assess the leukemia risk of occupational exposure to cyclophosphamide. Average task frequencies from the population of oncology nurses in the Netherlands and task-based dermal exposure intensities were used to calculate oncology nurses’ dermal exposure levels. A dermal absorption model in combination with a physiologically based pharmacokinetic model was used to assess the delivered dose of cyclophosphamide and its active metabolites in the bone marrow. This delivered dose was subsequently related to pharmacodynamic and epidemiological information from a longitudinal study with cyclophosphamide-treated patients to estimate the excess lifetime leukemia risk at age 80 for Dutch oncology nurses after 40 years of exposure to cyclophosphamide. The excess lifetime leukemia risk at age 80 of an exposed oncology nurse after 40 years of dermal exposure to cyclophosphamide was estimated to be 1.04 per million oncology nurses. This risk could potentially increase to a maximum of 154 per million if a nurse performs all cyclophosphamide-related tasks with the maximum frequency (as observed in this population) and is exposed to maximum exposure intensities for each task without using protective gloves for 40 years. This study indicates that the risk of an oncology nurse in a Dutch hospital with an average dermal exposure to cyclophosphamide is well below the maximum tolerable risk of one extra death from cancer per 250 deaths after 40 years of occupational exposure, and that this level is not exceeded in a worst-case scenario.

We recently found that renal carbonic anhydrase (CA) is involved in the reabsorption of inorganic nitrite (NO2−), an abundant reservoir of nitric oxide (NO) in tissues and cells. Impaired NO synthesis in the endothelium and decreased NO bioavailability in the circulation are considered major contributors to the development and progression of renal and cardiovascular diseases in different conditions including diabetes. Isolated human and bovine erythrocytic CAII and CAIV can convert nitrite to nitrous acid (HONO) and its anhydride N2O3 which, in the presence of thiols (RSH), are further converted to S-nitrosothiols (RSNO) and NO. Thus, CA may be responsible both for the homeostasis of nitrite and for its bioactivation to RSNO/NO. We hypothesized that enhanced excretion of nitrite in the urine may contribute to NO-related dysfunctions in the renal and cardiovascular systems, and proposed the urinary nitrate-to-nitrite molar ratio, i.e., UNOxR, as a measure of renal CA-dependent excretion of nitrite. Based on results from clinical and experimental animal studies, here, we report on a first evaluation of UNOxR. We determined UNOxR values in preterm neonates, healthy children, and adults, in children suffering from type 1 diabetes mellitus (T1DM) or Duchenne muscular dystrophy (DMD), in elderly subjects suffering from chronic rheumatic diseases, type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), or peripheral arterial occlusive disease (PAOD). We also determined UNOxR values in healthy young men who ingested isosorbide dinitrate (ISDN), pentaerythrityl tetranitrate (PETN), or inorganic nitrate. In addition, we tested the utility of UNOxR in two animal models, i.e., the LEW.1AR1-iddm rat, an animal model of human T1DM, and the APOE*3-Leiden.CETP mice, a model of human dyslipidemia. Mean UNOxR values were lower in adult patients with rheumatic diseases (187) and in T2DM patients of the DALI study (74) as compared to healthy elderly adults (660) and healthy young men (1500). The intra- and inter-variabilities of UNOxR were of the order of 50% in young and elderly healthy subjects. UNOxR values were lower in black compared to white boys (314 vs. 483, P = 0.007), which is in line with reported lower NO bioavailability in black ethnicity. Mean UNOxR values were lower in DMD (424) compared to healthy (730) children, but they were higher in T1DM children (1192). ISDN (3 × 30 mg) decreased stronger UNOxR compared to PETN (3 × 80 mg) after 1 day (P = 0.046) and after 5 days (P = 0.0016) of oral administration of therapeutically equivalent doses. In healthy young men who ingested NaNO3 (0.1 mmol/kg/d), UNOxR was higher than in those who ingested the same dose of NaCl (1709 vs. 369). In LEW.1AR1-iddm rats, mean UNOxR values were lower than in healthy rats (198 vs. 308) and comparable to those in APOE*3-Leiden.CETP mice (151).

The aim of the present study was to investigate the pharmacokinetics of oestriol in plasma in the dog after repeated oral administration of oestriol tablets, a preparation intended for the treatment of urinary incontinence in the bitch. The study was performed in six healthy, entire, adult female beagle dogs. The bitches were treated once daily with two tablets, containing 1 mg oestriol per tablet, for seven consecutive days (days 1-7). Blood samples were taken from the jugular vein before treatment, frequently on days 1, 3 and 7 of the treatment period and daily just before (Ctrough) and 1 h after dosing (Ct=1h). During the washout period samples were taken at a 24 h interval up to four days post-treatment. Oestriol concentrations were determined in plasma by radioimmunoassay. Pharmacokinetic parameters, AUC, Cmax and tmax, were determined from the plasma concentration-time curves using non-compartmental methods. The between animal variation in Cmax and the AUC was high. Individual values of the Cmax varied from 206 pg/ml (day 1) to 1128 pg/ml (day 7) and the AUC0-24 h from 789 pg.h/ml (day 1) to 5718 pg.h/ml (day 7). tmax occurred within 1 h. The mean Ctrough value was slightly above the pre-treatment level (38 ± 2 pg/ml vs. 18 ± 5 pg/ml). Within 48 h after the last treatment the concentrations had returned to the pre-treatment values. Cmax, and Ctrough did not increase during the treatment period, indicating that no accumulation occurred. A shoulder in the concentration-time curve around 8-12 h after treatment strongly suggested the existence of enterohepatic recirculation (EHR). The average relative contribution of the EHR to the AUC0-24 h was estimated to be 22%, 38% and 44% on days 1, 3 and 7, respectively. These mean values were calculated from five animals per time point, because one dog failed to show EHR on days 1 and 3 and was therefore excluded from the calculations. © 2003 Elsevier Science Ltd. All rights reserved.