International Journal of Sport Nutrition and Exercise Metabolism, 2022
This study aimed to investigate the effects of different exercise training programs on fasting pl... more This study aimed to investigate the effects of different exercise training programs on fasting plasma levels of oxylipins, endocannabinoids (eCBs), and eCBs-like molecules in middle-aged sedentary adults. A 12-week randomized controlled trial was conducted using a parallel group design. Sixty-five middle-aged adults (40–65 years old) were randomly assigned to: (a) no exercise (control group), (b) concurrent training based on international physical activity recommendations (PAR group), (c) high-intensity interval training (HIIT group), and (d) HIIT together with whole-body electromyostimulation (HIIT + EMS group). Plasma levels of oxylipins, eCBs, and eCBs-like molecules were determined in plasma samples before and after the intervention using targeted lipidomics. Body composition was assessed through dual-energy X-ray absorptiometry, and dietary intake through a food frequency questionnaire and three nonconsecutive 24-hr recalls. The physical activity recommendations, HIIT, and HIIT...
Describing glomerular filtration rate (GFR) maturation across the heterogeneous population of pre... more Describing glomerular filtration rate (GFR) maturation across the heterogeneous population of preterm and term neonates and infants is important to predict the clearance of renally cleared drugs. This study aims to describe the GFR maturation in (pre)term neonates and young infants (PNA < 90 days) using individual inulin clearance data (CLinulin). To this end, published GFR maturation models were evaluated by comparing their predicted GFR with CLinulin retrieved from literature. The best model was subsequently optimized in NONMEM V7.4.3 to better fit the CLinulin values. Our study evaluated seven models and collected 381 individual CLinulin values from 333 subjects with median (range) birthweight (BWb) 1880 g (580–4950), gestational age (GA) 34 weeks (25–43), current weight (CW) 1890 g (480–6200), postnatal age (PNA) 3 days (0–75), and CLinulin 2.20 ml/min (0.43–17.90). The De Cock 2014 model (covariates: BWb and PNA) performed the best in predicting CLinulin, followed by the Rho...
Pharmacogenetics is a newly emerging research area confronted with obvious scientific and ethical... more Pharmacogenetics is a newly emerging research area confronted with obvious scientific and ethical concerns not only from an academic and social perspective, but also on a regulatory level. An overview of ongoing and planned pharmacogenetic studies is needed to evaluate the current status and focus of research and to appraise the alignment of research themes relative to the unmet medical needs of the paediatric population. The objective of this review was to explore the current status, limitations and perspectives of pharmacogenomic and pharmacogenetic clinical research in the paediatric population from an academic, regulatory and industrial perspective. Results show a rather equal distribution of activities across the different research categories throughout the world. More than 50% of the research activities are related to exploratory studies aimed at establishing the connection between a given genetic trait and the risk associated with a pathology or disease. Based on this situati...
Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies, Jan 2, 2016
To compare the pharmacodynamics and pharmacokinetics of IV morphine after cardiac surgery in two ... more To compare the pharmacodynamics and pharmacokinetics of IV morphine after cardiac surgery in two groups of children-those with and without Down syndrome. Prospective, single-center observational trial. PICU in a university-affiliated pediatric teaching hospital. Twenty-one children with Down syndrome and 17 without, 3-36 months old, scheduled for cardiac surgery with cardiopulmonary bypass. A loading dose of morphine (100 μg/kg) was administered after coming off bypass; thereafter, morphine infusion was commenced at 40 μg/kg/hr. During intensive care, nurses regularly assessed pain and discomfort with validated observational instruments (COMFORT-Behavior scale and Numeric Rating Scale-for pain). These scores guided analgesic and sedative treatment. Plasma samples were obtained for pharmacokinetic analysis. Median COMFORT-Behavior and Numeric Rating Scale scores were not statistically significantly different between the two groups. The median morphine infusion rate during the first 2...
In life sciences, light microscopy is used to study specimens. On the organism-level a bright-fie... more In life sciences, light microscopy is used to study specimens. On the organism-level a bright-field representation present an overview for the whole shape of a specimen; the organ-level fluorescent staining representation supports in the interpretation of the detailed intrinsic structures. We present light microscopy axial-view imaging based on the Vertebrate Automated Screening Technology to acquire axial-view images for the organism and organs of zebrafish larvae. We obtain multi-modal 3D reconstruction using a profile-based method, from which we can derive the 3D measurements of volume and surface area. In this method, we employ a microscope camera calibration using voxel residual volume maximization algorithm. We intuitively align and fuse the obtained multi-models. Experimental results show natural visualization both for the whole organism and organ of zebrafish larvae; subsequently accurate 3D measurements are obtained. This method is very suitable for high-throughput research in which knowledge on size and shape is relevant to the understanding for development, effects of compounds or drugs.
International Journal of Sport Nutrition and Exercise Metabolism, 2022
This study aimed to investigate the effects of different exercise training programs on fasting pl... more This study aimed to investigate the effects of different exercise training programs on fasting plasma levels of oxylipins, endocannabinoids (eCBs), and eCBs-like molecules in middle-aged sedentary adults. A 12-week randomized controlled trial was conducted using a parallel group design. Sixty-five middle-aged adults (40–65 years old) were randomly assigned to: (a) no exercise (control group), (b) concurrent training based on international physical activity recommendations (PAR group), (c) high-intensity interval training (HIIT group), and (d) HIIT together with whole-body electromyostimulation (HIIT + EMS group). Plasma levels of oxylipins, eCBs, and eCBs-like molecules were determined in plasma samples before and after the intervention using targeted lipidomics. Body composition was assessed through dual-energy X-ray absorptiometry, and dietary intake through a food frequency questionnaire and three nonconsecutive 24-hr recalls. The physical activity recommendations, HIIT, and HIIT...
Describing glomerular filtration rate (GFR) maturation across the heterogeneous population of pre... more Describing glomerular filtration rate (GFR) maturation across the heterogeneous population of preterm and term neonates and infants is important to predict the clearance of renally cleared drugs. This study aims to describe the GFR maturation in (pre)term neonates and young infants (PNA < 90 days) using individual inulin clearance data (CLinulin). To this end, published GFR maturation models were evaluated by comparing their predicted GFR with CLinulin retrieved from literature. The best model was subsequently optimized in NONMEM V7.4.3 to better fit the CLinulin values. Our study evaluated seven models and collected 381 individual CLinulin values from 333 subjects with median (range) birthweight (BWb) 1880 g (580–4950), gestational age (GA) 34 weeks (25–43), current weight (CW) 1890 g (480–6200), postnatal age (PNA) 3 days (0–75), and CLinulin 2.20 ml/min (0.43–17.90). The De Cock 2014 model (covariates: BWb and PNA) performed the best in predicting CLinulin, followed by the Rho...
Pharmacogenetics is a newly emerging research area confronted with obvious scientific and ethical... more Pharmacogenetics is a newly emerging research area confronted with obvious scientific and ethical concerns not only from an academic and social perspective, but also on a regulatory level. An overview of ongoing and planned pharmacogenetic studies is needed to evaluate the current status and focus of research and to appraise the alignment of research themes relative to the unmet medical needs of the paediatric population. The objective of this review was to explore the current status, limitations and perspectives of pharmacogenomic and pharmacogenetic clinical research in the paediatric population from an academic, regulatory and industrial perspective. Results show a rather equal distribution of activities across the different research categories throughout the world. More than 50% of the research activities are related to exploratory studies aimed at establishing the connection between a given genetic trait and the risk associated with a pathology or disease. Based on this situati...
Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies, Jan 2, 2016
To compare the pharmacodynamics and pharmacokinetics of IV morphine after cardiac surgery in two ... more To compare the pharmacodynamics and pharmacokinetics of IV morphine after cardiac surgery in two groups of children-those with and without Down syndrome. Prospective, single-center observational trial. PICU in a university-affiliated pediatric teaching hospital. Twenty-one children with Down syndrome and 17 without, 3-36 months old, scheduled for cardiac surgery with cardiopulmonary bypass. A loading dose of morphine (100 μg/kg) was administered after coming off bypass; thereafter, morphine infusion was commenced at 40 μg/kg/hr. During intensive care, nurses regularly assessed pain and discomfort with validated observational instruments (COMFORT-Behavior scale and Numeric Rating Scale-for pain). These scores guided analgesic and sedative treatment. Plasma samples were obtained for pharmacokinetic analysis. Median COMFORT-Behavior and Numeric Rating Scale scores were not statistically significantly different between the two groups. The median morphine infusion rate during the first 2...
In life sciences, light microscopy is used to study specimens. On the organism-level a bright-fie... more In life sciences, light microscopy is used to study specimens. On the organism-level a bright-field representation present an overview for the whole shape of a specimen; the organ-level fluorescent staining representation supports in the interpretation of the detailed intrinsic structures. We present light microscopy axial-view imaging based on the Vertebrate Automated Screening Technology to acquire axial-view images for the organism and organs of zebrafish larvae. We obtain multi-modal 3D reconstruction using a profile-based method, from which we can derive the 3D measurements of volume and surface area. In this method, we employ a microscope camera calibration using voxel residual volume maximization algorithm. We intuitively align and fuse the obtained multi-models. Experimental results show natural visualization both for the whole organism and organ of zebrafish larvae; subsequently accurate 3D measurements are obtained. This method is very suitable for high-throughput research in which knowledge on size and shape is relevant to the understanding for development, effects of compounds or drugs.
Zebrafish larvae are increasingly used for pharmacological research, but internal drug exposure i... more Zebrafish larvae are increasingly used for pharmacological research, but internal drug exposure is often not measured. Understanding pharmacokinetics is necessary for reliable translation of pharmacological results to higher vertebrates, including humans. Quantification of drug clearance and distribution requires measurements of blood concentrations. Additionally, measuring drug metabolites is of importance to understand clearance in this model organism mechanistically. We therefore mechanistically study and quantify pharmacokinetics in zebrafish larvae, and compare this to higher vertebrates, using paracetamol (acetaminophen) as paradigm compound. A method was developed to sample blood from zebrafish larvae five days post fertilization. Blood concentrations of paracetamol and its major metabolites, paracetamol-glucuronide and paracetamol-sulphate, were measured. Blood concentration data were combined with measured amounts in larval homogenates and excreted amounts and simultaneously analysed through non-linear mixed effects modelling, quantifying absolute clearance and distribution volume. Blood sampling from zebrafish larvae was most successful from the posterior cardinal vein with median volume (interquartile range) of 1.12 (0.676-1.66) nL per blood sample. Samples were pooled (n=15-35) to reach measurable levels. Paracetamol blood concentrations at steady state were only 10% of the external paracetamol concentration. Paracetamol-sulphate was the major metabolite and its formation was quantified using a time-dependent metabolic formation rate. Absolute clearance and distribution volume correlated well to reported values in higher vertebrates, including humans. Based on blood concentrations and advanced data analysis, the mechanistic and quantitative understanding of paracetamol pharmacokinetics in zebrafish larvae has been established. This will improve the translational value of this vertebrate model organism in drug discovery and development.
Zebrafish larvae are increasingly used in pharmacological and toxicological studies, but it is of... more Zebrafish larvae are increasingly used in pharmacological and toxicological studies, but it is often overlooked that internal exposure to exogenous compounds, rather than the incubation medium concentration, is driving observed effects. Moreover, as the zebrafish larva is a developing organism, continuous physiological changes impact pharmacokinetic or toxicokinetic processes like the absorption and elimination of exogenous compounds, influencing the interpretation of observations and conclusions drawn from experiments at different larval ages. Here, using paracetamol as paradigm compound, mathematical modelling is used to quantify absorption and elimination rates from internal exposure over time profiles after waterborne treatment, as well as changes in these parameters in post-hatching larvae of 3, 4, and 5 days post fertilisation (dpf). An increase of 106% in absorption rate was observed between 3 and 4 dpf, but no further increase at 5 dpf, and an increase of 17.5% in elimination rate for each dpf. paracetamol clearance, determined from elimination rate constants and reported total larval volumes of 253, 263, and 300 nL at 3, 4, and 5 dpf respectively, correlates best with higher vertebrates at 5 dpf. This suggests that when studying direct effects of exogenous compounds, experiments with zebrafish larvae are best performed at 5 dpf.
To advance the systems approach in pharmacology, experimental models and computational methods ne... more To advance the systems approach in pharmacology, experimental models and computational methods need to be integrated from early drug discovery onward. Here, we propose outside-in model development, a model identification technique to understand and predict the dynamics of a system without requiring prior biological and/or pharmacological knowledge. The advanced data required could be obtained by whole vertebrate, high-throughput, low-resource dose-exposure-effect experimentation with the zebrafish larva. Combinations of these innovative techniques could improve early drug discovery.
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Papers by Elke Krekels