Superheavy dark matter and ultrahigh energy cosmic rays

The phase of inflationary expansion in the early universe produces superheavy relics in a mass window between 10^{12} GeV and 10^{14} GeV. Decay or annihilation of these superheavy relics can explain the observed ultrahigh energy cosmic rays beyond the Greisen-Zatsepin-Kuzmin cutoff. We emphasize that the pattern of cosmic ray arrival directions with energies beyond 20 EeV will decide between the different proposals for the origin of ultrahigh energy cosmic rays.Comment: Based on an invited talk given by RD at Theory Canada 1, Vancouver, June 2-5, 200

Sequestration of Voriconazole and Vancomycin Into Contemporary Extracorporeal Membrane Oxygenation Circuits: Anin vitroStudy

Background: Bacterial and fungal infections are common and often contribute to death in patients undergoing extracorporeal membrane oxygenation (ECMO). Drug disposition is altered during ECMO, and adsorption in the circuit is an established causative factor. Vancomycin and voriconazole are widely used, despite the lack of evidence-based prescription guidelines. Objective: The objective of this study was to determine the extraction of voriconazole and vancomycin by the Xenios/Novalung ECMO circuits. Methods: We have set up nine closed-loop ECMO circuits, consisting of four different iLAActivve® kits for neonatal, pediatric, and adult support: three iLA-ActivveMiniLung® petite kits, two iLA-ActivveMiniLung® kits, two iLA-ActivveiLA® kits, and two iLA-Activve X-lung® kits. The circuits were primed with whole blood and maintained at physiologic conditions for 24 h. Voriconazole and vancomycin were injected as a single-bolus age-related dose into the circuits. Pre-membrane (P2) blood samples were obtained at baseline and after drug injection at 2, 10, 30, 180, 360 min, and 24 h. A control sample at 2 min was collected for spontaneous drug degradation testing at 24 h. Results: Seventy-two samples were analyzed in triplicate. The mean percentage of drug recovery at 24 h was 20% for voriconazole and 62% for vancomycin. Conclusions: The extraction of voriconazole and vancomycin by contemporary ECMO circuits is clinically relevant across all age-related circuit sizes and may result in reduced drug exposure in vivo

Evidence-based drug treatment for special patient populations through model-based approaches

The majority of marketed drugs remain understudied in some patient populations such as pregnant women, paediatrics, the obese, the critically-ill, and the elderly. As a consequence, currently used dosing regimens may not assure optimal efficacy or minimal toxicity in these patients. Given the vulnerability of some subpopulations and the challenges and costs of performing clinical studies in these populations, cutting-edge approaches are needed to effectively develop evidence-based and individualized drug dosing regimens. Five key issues are presented that are essential to support and expedite the development of drug dosing regimens in these populations using model-based approaches: 1) model development combined with proper validation procedures to extract as much valid information from available study data as possible, with limited burden to patients and costs; 2) integration of existing data and the use of prior pharmacological and physiological knowledge in study design and data analysis, to further develop knowledge and avoid unnecessary or unrealistic (large) studies in vulnerable populations; 3) clinical proof-of-principle in a prospective evaluation of a developed drug dosing regimen, to confirm that a newly proposed regimen indeed results in the desired outcomes in terms of drug concentrations, efficacy, and/or safety; 4) pharmacodynamics studies in addition to pharmacokinetics studies for drugs for which a difference in disease progression and/or in exposure-response relation is anticipated compared to the reference population; 5) additional efforts to implement developed dosing regimens in clinical practice once drug pharmacokinetics and pharmacodynamics have been characterized in special patient populations. The latter remains an important bottleneck, but this is essential to truly realize evidence-based and individualized drug dosing for special patient populations. As all tools required for this purpose are available, we have the moral and societal obligation to make safe and effective pharmacotherapy available for these patients to

Developmental changes rather than repeated administration drive paracetamol glucuronidation in neonates and infants

Purpose: Based on recovered metabolite ratios in urine, it has been concluded that paracetamol glucuronidation may be up-regulated upon multiple dosing. This study investigates paracetamol clearance in neonates and infants after single and multiple dosing using a population modelling approach. Methods: A population pharmacokinetic model was developed in NONMEM VI, based on paracetamol plasma concentrations from 54 preterm and term neonates and infants, and on paracetamol, paracetamol-glucuronide and paracetamol-sulphate amounts in urine from 22 of these patients. Patients received either a single intravenous propacetamol dose or up to 12 repeated doses. Results: Paracetamol and metabolite disposition was best described with one-compartment models. The formation clearance of paracetamol-sulphate was 1.46 mL/min/kg1.4, which was about 5.5 times higher than the formation clearance of the glucuronide of 0.266 mL/min/kg. The renal excretion rate constants of both met

Tragedy revisited

“Freedom in a commons brings ruin to all.” So argued ecologist Garrett Hardin in “The Tragedy of the Commons” in the 13 December 1968 issue of Science (1). Hardin questioned society's ability to manage shared resources and avoid an environmentally and socially calamitous free-for-all. In the 50 years since, the essay has influenced discussions ranging from climate change (see page 1217) to evolution, from infectious disease to the internet, and has reached far beyond academic literature—but not without criticism. Considerable work, notably by Nobelist Elinor Ostrom (2), has challenged Hardin, particularly his emphasis on property rights and government regulatory leviathans as solutions. Instead, research has documented contexts, cases, and principles that reflect the ability of groups to collectively govern common resources. To mark this anniversary and celebrate the richness of research and practice around commons and cooperation, Science invited experts to share some contemporary views on such tragedies and how to avert them. —Brad Wibl

Paracetamol in Older People: Towards Evidence-Based Dosing?

Paracetamol is the most commonly used analgesic in older people, and is mainly dosed according to empirical dosing guidelines. However, the pharmacokinetics and thereby the effects of paracetamol can be influenced by physiological changes occurring with ageing. To investigate the steps needed to reach more evidence-based paracetamol dosing regimens in older people, we applied the concepts used in the paediatric study decision tree. A search was performed to retrieve studies on paracetamol pharmacokinetics and safety in older people (> 60 years) or studies that performed a (sub) analysis of pharmacokinetics and/or safety in older people. Of 6088 articles identified, 259 articles were retained after title and abstract screening. Further abstract and full-text screening identified 27 studies, of which 20 described pharmacokinetics and seven safety. These studies revealed no changes in absorption with ageing. A decreased (3.9–22.9%) volume of distribution (Vd) in robust older subjects and a further decreased Vd (20.3%) in frail older compared with younger subjects was apparent. Like Vd, age and frailty decreased paracetamol clearance (29–45.7 and 37.5%) compared with younger subjects. Due to limited and heterogeneous evidence, it was difficult to draw firm and meaningful conclusions on changed risk for paracetamol safety in older people. This review is a first step towards bridging knowledge gaps to move to evidence-based paracetamol dosing in older subjects. Remaining knowledge gaps are safety when using therapeutic dosages, pharmacokinetics changes in frail older people, and to what extent changes in paracetamol pharmacokinetics should lead to a change in dosage in frail and robust older people

Integration of Placental Transfer in a Fetal–Maternal Physiologically Based Pharmacokinetic Model to Characterize Acetaminophen Exposure and Metabolic Clearance in the Fetus

Background and Objective: Although acetaminophen is frequently used during pregnancy, little is known about fetal acetaminophen pharmacokinetics. Acetaminophen safety evaluation has typically focused on hepatotoxicity, while other events (fetal ductal closure/constriction) are also relevant. We aimed to develop a fetal–maternal physiologically based pharmacokinetic (PBPK) model (f-m PBPK) to quantitatively predict placental acetaminophen transfer, characterize fetal acetaminophen exposure, and quantify the contributions of specific clearance pathways in the term fetus. Methods: An acetaminophen pregnancy PBPK model was extended with a compartment representing the fetal liver, which included maturation of relevant enzymes. Different approaches to describe placental transfer were evaluated (ex vivo cotyledon perfusion experiments, placental transfer prediction based on Caco-2 cell permeability or physicochemical properties [MoBi®]). Predicted maternal and fetal acetaminophen profiles were compared with in vivo observations. Results: Tested approaches to predict placental t

Pharmacological sedation management in the paediatric intensive care unit

Objective: This review addresses sedation management on paediatric intensive care units and possible gaps in the knowledge of optimal sedation strategies. We present an overview of the commonly used sedatives and their pharmacokinetic and pharmacodynamic considerations in children, as well as the ongoing studies in this field. Also, sedation guidelines and current sedation strategies and assessment methods are addressed. Key findings: This review shows that evidence and pharmacokinetic data are scarce, but fortunately, there is an active research scene with promising new PK and PD data of sedatives in children using new study designs with application of advanced laboratory methods and modelling. The

Successful Use of [14C]Paracetamol Microdosing to Elucidate Developmental Changes in Drug Metabolism

Background: We previously showed the practical and ethical feasibility of using [14C]-microdosing for pharmacokinetic studies in children. We now aimed to show that this approach can be used to elucidate developmental changes in drug metabolism, more specifically, glucuronidation and sulfation, using [14C]paracetamol (AAP). Methods: Infants admitted to the intensive care unit received a single oral [14C]AAP microdose while receiving intravenous therapeutic AAP every 6 h. [14C]AAP pharmacokinetic parameters were estimated. [14C]AAP and metabolit