Articles and other publications by RIVM employees: Recent submissions
Now showing items 1-20 of 3908
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A physiologically based pharmacokinetic model to predict pegylated liposomal doxorubicin disposition in rats and human.The use of nanoparticles (NPs) can support an enhancement of drug distribution, resulting in increased drug penetration into key tissues. Experimental in vitro data can be integrated into computational approaches to simulate NP absorption, distribution, metabolism and elimination (ADME) processes and provide quantitative pharmacokinetic predictions. The aim of this study is to develop a novel mechanistic and physiologically based pharmacokinetic (m-PBPK) model to predict the biodistribution of NPs focusing on Doxil. The main processes underpinning NPs ADME were represented considering molecular and cellular mechanisms such as stability in biological fluids, passive permeability and uptake activity by macrophages. A whole-body m-PBPK rat and human models were designed in Simbiology v. 9.6.0 (MATLAB R2019a). The m-PBPK models were successfully qualified across doxorubicin and Doxil® in both rat and human since all PK parameters AUC0-inf, Cmax, t1/2, Vd and Cl were within twofold, with an AUC0-inf absolute average-fold error (AAFE) value of 1.23 and 1.16 and 1.76 and 1.05 for Doxorubicin and Doxil® in rat and human, respectively. The time to maximum concentration in tissues for doxorubicin in both rat and human models was before 30 min of administration, while for Doxil®, the tmax was after 24 h of administration. The organs that accumulate most NP are the spleen, liver and lungs, in both models. The m-PBPK represents a predictive platform for the integration of in vitro and formulation parameters in a physiological context to quantitatively predict the NP biodistribution. Schematic diagram of the whole-body m-PBPK models developed for Doxil® in rat and human physiology.
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Photochemical degradation pathways of cell-free antibiotic resistance genes in water under simulated sunlight irradiation: Experimental and quantum chemical studies.The presence of antibiotic resistance genes (ARGs) in the environment poses a threat to human health and therefore their environmental behavior needs to be studied urgently. A systematic study was conducted on the photodegradation pathways of the cell-free tetracycline resistance gene (Tc-ARG) under simulated sunlight irradiation. The results showed that Tc-ARG can undergo direct photodegradation, which significantly reduces its horizontal transfer efficiency. Suwannee River fulvic acid (SRFA) promoted the photodegradation of Tc-ARG and further inhibited its horizontal transfer by generating reactive intermediates. The photodegradation of Tc-ARG was attributed to degradation of the four bases (G, C, A, T) and the deoxyribose group. Quantum chemical calculations showed that the four bases could be oxidized by the hydroxyl radical (HO) through addition and H-abstraction reactions. The main oxidative product 8-oxo-dG was detected. This product was generated through the addition reaction of G-C with HO, subsequent to dissolved oxygen initiated H-abstraction and H2O catalyzed H-transfer reactions. The predicted maximum photodegradation rates of Tc-ARG in the Yellow River estuary were 0.524, 0.937, and 0.336 h-1 in fresh water, estuary water, and seawater, respectively. This study furthermore revealed the microscopic photodegradation pathways and obtained essential degradation parameters of Tc-ARG in sunlit surface water.
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Global spatial dynamics and vaccine-induced fitness changes of .As with other pathogens, competitive interactions between Bordetella pertussis strains drive infection risk. Vaccines are thought to perturb strain diversity through shifts in immune pressures; however, this has rarely been measured because of inadequate data and analytical tools. We used 3344 sequences from 23 countries to show that, on average, there are 28.1 transmission chains circulating within a subnational region, with the number of chains strongly associated with host population size. It took 5 to 10 years for B. pertussis to be homogeneously distributed throughout Europe, with the same time frame required for the United States. Increased fitness of pertactin-deficient strains after implementation of acellular vaccines, but reduced fitness otherwise, can explain long-term genotype dynamics. These findings highlight the role of vaccine policy in shifting local diversity of a pathogen that is responsible for 160,000 deaths annually.