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Contains fulltext : 209000.pdf (publisher's version ) (Open Access), Human renal membrane transporters play key roles in the disposition of renally cleared drugs and endogenous substrates, but their ontogeny is largely unknown. Using 184 human postmortem frozen renal cortical tissues (preterm newborns to adults) and a subset of 62 tissue samples, we measured the mRNA levels of 11 renal transporters and the transcription factor pregnane X receptor (PXR) with quantitative real-time polymerase chain reaction, and protein abundance of nine transporters using liquid chromatography tandem mass spectrometry selective reaction monitoring, respectively. Expression levels of p-glycoprotein, urate transporter 1, organic anion transporter 1, organic anion transporter 3, and organic cation transporter 2 increased with age. Protein levels of multidrug and toxin extrusion transporter 2-K and breast cancer resistance protein showed no difference from newborns to adults, despite age-related changes in mRNA expression. Multidrug and toxin extrusion transporter 1, glucose transporter 2, multidrug resistance-associated protein 2, multidrug resistance-associated protein 4 (MRP4), and PXR expression levels were stable. Using immunohistochemistry, we found that MRP4 localization in pediatric samples was similar to that in adult samples. Collectively, our study revealed that renal drug transporters exhibited different rates and patterns of maturation, suggesting that renal handling of substrates may change with age.

Contains fulltext : 207196.pdf (publisher's version ) (Closed access), In this exploratory study we aimed to select the most valid and feasible accelerometer to measure daily physical activity at home in 10 children with mitochondrial disease. Using the experimentally-selected GENEActiv, good to excellent short- and long-term test-retest reliability of daily physical activity was found. Especially in children with more severe limitations daily physical activity seemed more stable and less susceptible to weather conditions. Moreover, small standard errors of measurement were found, indicating high precision of this measuring method. We conclude that measuring daily physical activity using accelerometry is a promising outcome measure for future studies in this unique population.

Purpose: Ibuprofen is the drug of choice for treatment of patent ductus arteriosus (PDA). There is accumulating evidence that current ibuprofen-dosing regimens for PDA treatment are inadequate. We aimed to propose an improved dosing regimen, based on all current knowledge. Methods: We performed a literature search on the clinical pharmacology and effectiveness of ibuprofen. (R)- and (S)-ibuprofen plasma concentration-time profiles of different dosing regimens were simulated using a population pharmacokinetic model and evaluated to obtain a safe, yet likely more efficacious ibuprofen exposure. Results: The most effective intravenous ibuprofen dosing in previous clinical trials included a first dose of 20 mg kg−1 followed by 10 mg kg−1 every 24 h. Simulations of this dosing regimen show an (S)-ibuprofen trough concentration of 43 mg L−1 is reached at 48 h, which we assumed the target through concentration. We show that this target can be reached with a first dose of 18 mg kg−1, followed by 4 mg kg−1 every 12 h. After 96 h postnatal age, the dose should be increased to 5 mg kg−1 every 12 h due to maturation of clearance. This twice-daily dosing has the advantage over once-daily dosing that an effective trough level may be maintained, while peak concentrations are substantially (22%) lower. Conclusions: We propose to improve intermittent ibuprofen-dosing regimens by starting with a high first dose followed by a twice-daily maintenance dosing regimen that requires increase over time and should be continued until sufficient effect has been achieved.

Contains fulltext : 182324.pdf (publisher's version ) (Open Access), BACKGROUND: Mitochondrial disorders are a clinically, biochemically and genetically heterogeneous group of multi-system diseases, with an unmet medical need for treatment. KH176 is an orally bio-available small molecule under development for the treatment of mitochondrial(-related) diseases. The compound is a member of a new class of drugs, acting as a potent intracellular redox-modulating agent essential for the control of oxidative and redox pathologies. The aim of this randomized, placebo controlled, double-blinded phase 1 study was to test safety, tolerability and pharmacokinetics of single and multiple doses of KH176 in healthy male volunteers. Putative effects on redox related biomarkers were explored. RESULTS: KH176 was well tolerated up to and including a single dose of 800 mg and multiple doses of 400 mg b.i.d. for 7 Days. However, when the QT interval was corrected for heart rate, administration of single doses of 800 and 2000 mg and at a multiple dose of 400 mg KH176 had marked effects. Post-hoc analysis of the ECGs showed clear changes in cardiac electrophysiology at single doses of 800 and 2000 mg and multiple doses of 400 mg b.i.d.. At lower doses, detailed ECG analysis showed no changes in electrophysiology compared to placebo. Exposure-response modelling of the cardiac intervals revealed an exposure range of KH176 without effects on cardiac conduction and provided a threshold of 1000 ng/mL above which changes in intervals could occur. After single- and multiple-dose administration, the pharmacokinetics of KH176 was more than dose proportional. KH176 accumulated to a small extent and food only slightly affected the pharmacokinetics of KH176, which was considered clinically irrelevant. Renal excretion of unchanged KH176 and its metabolite represents a minor pathway in the elimination of KH176. As expected in healthy volunteers no effects on redox biomarkers were observed. CONCLUSION: The study deemed that KH176 is well tolerated up to single doses of 8

Results: Ten infants (aged 0.1–83.1 months) were included; one was excluded as he vomited shortly after administration. In nine patients, [14C]AAP and metabolites in blood samples were detectable at expected concentrations: median (range) maximum concentration (Cmax) [14C]AAP 1.68 (0.75–4.76) ng/L, [14C]AAP-Glu 0.88 (0.34–1.55) ng/L, and [14C]AAP-4Sul 0.81 (0.29–2.10) ng/L. Dose-normalized oral [14C]AAP Cmax approached median intravenous average concentrations (Cav): 8.41 mg/L (3.75–23.78 mg/L) and 8.87 mg/L (3.45–12.9 mg/L), respectively.Conclusions: We demonstrate the feasibility of using a [14C]labeled microdose to study AAP pharmacokinetics, including metabolite disposition, in young children.Background: Pediatric drug development is hampered by practical, ethical, and scientific challenges. Microdosing is a promising new method to obtain pharmacokinetic data in children with minimal burden and minimal risk. The use of a labeled oral microdose offers the added benefit to study intestinal and hepatic drug disposition in children already receiving an intravenous therapeutic drug dose for clinical reasons.Methods: In an open-label microdose pharmacokinetic pilot study, infants (0–6 years of age) received a single oral [14C]AAP microdose (3.3 ng/kg, 60 Bq/kg) in addition to intravenous therapeutic doses of AAP (15 mg/kg intravenous every 6 h). Blood samples were taken from an indwelling catheter. AAP blood concentrations were measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS) and [14C]AAP and metabolites ([14C]AAP-Glu and [14C]AAP-4Sul) were measured by accelerator mass spectrometry.Objective: The objective of this study was to present pilot data of an oral [14C]paracetamol [acetaminophen (AAP)] microdosing study as proof of concept to study developmental pharmacokinetics in children.

Many drugs prescribed to children are drug transporter substrates. Drug transporters are membrane-bound proteins that mediate the cellular uptake or efflux of drugs and are important to drug absorption and elimination. Very limited data are available on the effect of age on transporter expression. Our study assessed age-related gene expression of hepatic and intestinal drug transporters. Multidrug resistance protein 2 (MRP2), organic anion transporting polypeptide 1B1 (OATP1B1), and OATP1B3 expression was determined in postmortem liver samples (fetal n = 6, neonatal n = 19, infant n = 7, child n = 2, adult n = 11) and multidrug resistance 1 (MDR1) expression in 61 pediatric liver samples. Intestinal expression of MDR1, MRP2, and OATP2B1 was determined in surgical small bowel samples (neonates n = 15, infants n = 3, adults n = 14). Using real-time reverse-transcription polymerase chain reaction, we measured fetal and pediatric gene expression relative to 18S rRNA (liver) and villin (intestines), and we compared it with adults using the 22 -Delta;Delta;Ct method. Hepatic expression of MRP2, OATP1B1, and OATP1B3 in all pediatric age groups was significantly lower than in adults. Hepatic MDR1 mRNA expression in fetuses, neonates, and infants was significantly lower than in adults. Neonatal intestinal expressions of MDR1 and MRP2 were comparable to those in adults. Intestinal OATP2B1 expression in neonates was significantly higher than in adults. We provide new data that show organ- and transporter-dependent differences in hepatic and intestinal drug transporter expression in an age-dependent fashion. This suggests that substrate drug absorption mediated by these transp

RIVM rapport:De studie Landelijke registratie klinische XTC-incidenten is bedoeld om gedurende een jaar het voorkomen, de ernst en omstandigheden van XTC intoxicaties, waarbij opname in een Nederlands ziekenhuis heeft plaatsgevonden, in kaart te brengen. Door middel van analytisch-toxicologisch onderzoek van serum, urine en overgebleven tabletten werd nagegaan of de waargenomen intoxicatie verschijnselen al dan niet samenhangen met het "XTC"-gebruik. Tevens werd onderzocht welke actieve bestanddelen van de ingenomen producten verantwoordelijk geacht kunnen worden voor het klinisch beeld. In het onderzoek werden 36 mannen en 14 vrouwen geincludeerd van wie het merendeel 18 tot 28 jaar oud was. Slechts 5 patienten (10 %) hadden de "XTC" op een houseparty gebruikt. Daarentegen gebruikte 60 % van de patinten "XTC" thuis of in een bar of disco. De overige 30 % nam bewust een intentionele overdosering of kreeg de "XTC" accidenteel binnen. Vrijwel alle patienten hadden naast "XTC" nog andere middelen ingenomen, meestal alcohol. Van de patienten bleek 80 % mild geintoxiceerd te zijn, waarbij opwinding, motorische onrust, tachycardie, mydriasis, misselijkheid en een overmatige zweetproductie op de voorgrond stonden. Daarnaast was 20 % ernstig geintoxiceerd met symptomen als hypo- of hypertensie, convulsies of coma.De analyses bevestigden dat deze groep "XTC" gebruikers feitelijk een groep van poly-drug-gebruikers is, die tegelijk verschillende andere middelen (zoals alcohol, cocaine, amfetamine, cannabis en gamma-hydroxy-boterzuur (GHB)) binnen heeft gekregen. Door serum- en urineanalyses te vergelijken met de gerapporteerde inname werd bevestigd dat "XTC" een verzamelnaam is voor verschillende actieve stoffen. In deze studie werden 17 verschillende verbindingen (zoals MDA, MDMA, amfetamine, 2-CB, MDDM, 2-CT-2) aangetroffen die de patienten binnen hadden gekregen zonder dat de inname daarvan uit de anamnese is gebleken. Er was geen verschil in ernst van het klinisch beeld tussen de mono, The present study is a registration during one year, of the extent, the severity and the circumstances of acute "XTC" intoxications for which admission was considered necessary in a hospital in the Netherlands. The clinical phenomena as well as serum and urine samples of patients suspected of having used "XTC" were analysed. This drug screening made it possible to relate the symptoms to the substances that were found present in the urine or serum samples of each patient.36 men and 14 women were included in the study and most of them were 18 - 28 years of age. Only five patients (10%) had used "XTC" at a mega-dance-party and 60% of the patients had used the "XTC" at home, or in a bar or disco. The other 30 % of the patients took the tablets accidently or in a suicidal attempt. Nearly all the patients had used one or more substances besides "XTC", mostly alcohol. Of the patients 80% were mildly intoxicated, with symptoms as restlessness, tachycardia, mydriasis, nausea and perspiration. In addition to these, 20 % of the patients were severely intoxicated, with symptoms such as hypo- or hypertension, convulsions or coma. One patient died.The analysis confirmed that most patients had used several drugs (such as alcohol, cocaine, amphetamin, cannabis and Gamma-hydroxy-butyric-acid (GHB)) besides "XTC". Moreover, by comparing the serum and urine results with the reported intake, it became clear that the exposure varied widely. In this study 17 different substances (such as MDA, MDMA, amphetamin, 2-CB, MDDM, 2-CT-2 and ephedrin) were found. There was no difference in clinical severity between the mono MDMA and MDEA intoxications and the rest of the study population, with the exception of GHB. In this study the reported number of hospital admissions due to the "XTC" use was relatively low and of these patients 20% were severely intoxicated. This study confirms that the content of "XTC" tablets is heterogeneous and that concomitant drug abuse is a risk factor. When one wants

RIVM rapport:Regelmatig worden het Nationaal Vergiftigingen Informatie Centrum van het Rijksinstituut voor Volksgezondheid en Milieu en de polikliniek Medische Toxicologie van het Academisch Ziekenhuis Utrecht geconfronteerd met vragen van artsen die te maken hebben met personen met een verhoogde blootstelling aan lood. Om deze vragen te kunnen beantwoorden is het noodzakelijk inzicht te hebben in de kinetiek van lood in het menselijk lichaam. In deze studie is een model ontwikkeld dat als hulpmiddel gebruikt kan worden bij het tot stand brengen van dit inzicht. Vervolgens wordt aan de hand van computersimulaties het verloop van een chronisch verhoogde loodbelasting en het nut van chelatietherapie beschreven., Although lead pollution, and thus lead intoxication, should be a decreasing problem in Western society, the Dutch Poison Control Centre and the medical toxicology outpatient Department of the Utrecht University Hospital are still often faced with patients with worrisome blood lead concentrations. Understanding the behaviour of lead in the human body is essential in dealing with these problems. Therefore a kinetic model which can explain this behaviour has been developed. Furthermore, the situation of a high lead burden is considered and an insight into the events surrounding treatment of these patients is presented.

Dit verslag beschrijft het ontwerp van een systeem voor het optimaliseren, voor wat betreft de kosten, van een ruraal telefoonnetwerk, dat opgebouwd is volgens de concepten van het op het laboratorium voor Automatische Verkeerssystemen in ontwikkeling zijnde rurale telefoonsysteem voor ontwikkelingslanden., Applied Sciences, Telecommunicatie- en Verkeersbegeleidingssystemen, Automatische Verkeerssystemen