Intravenous paracetamol and intraocular pressure reduction: Mannitol may also be involved

Karel Allegaert1,2 1Intensive Care, Department of Surgery, Erasmus MC Sophia Children’s Hospital, Rotterdam, the Netherlands; 2Department of Development and Regeneration, KU Leuven, BelgiumI read, with great interest, the paper on the intraocular pressure-lowering properties of intravenous paracetamol (acetaminophen) recently published in this journal by van den Heever and Meyer.1 The authors documented a decrease from baseline in mean intraocular pressure of 15.7% in a 6-hour time interval following intravenous paracetamol (1 g Perfalgan®, Bristol-Myers Squibb, New York, NY, USA) administration. This mean decrease was moderate but relevant when compared to, for example, topical timolol (–25.3%, single drop 0.5% timolol maleate) or oral acetazolamide (–23.1%, 250 mg). Although the authors provided potential relevant mechanistic arguments in support of a link between paracetamol administration and intraocular pressure through the endocannabinoid system, we would like to draw attention to the fact that – when intravenous paracetamol is administered – a relevant amount of mannitol is coadministered.View the original paper by van den Heever and Meye

Catch-Up growth in former preterm neonates: no time to waste

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EFFECT OF PROTEIN OXIDATION ON PARTICLE SIZE OF MYOFIBRILS

In order to study the effect of protein oxidation on the structure of myofibrils, extracted myofibrils from porcine longissimus dorsi muscle were incubated with different concentrations of the oxidant NaClO (0, 5, 10, 20 and 40 mM) at 5 ºC for 16 h. Increasing concentrations of NaClO led to a greater loss of free thiols and a larger particle size (in terms of D(v, 0.1), D(v, 0.5), D(v, 0.9), D(3, 2) and D(4, 3)) of myofibrils. Light microscope imaging showed that the myofibrils oxidized in 40 mM NaClO were less broken as compared to the non-oxidized group (0 mM NaClO). The increased structural integrity of myofibrils is likely caused by oxidation-induced protein cross-links, which resulted in a larger particle size when the myofibrils were subjected to homogenization

Catch-up growth in former preterm neonates: No time to waste

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Dysphagia in children with esophageal atresia: current diagnostic options

© 2017 Georg Thieme Verlag KGDysphagia or swallowing disorder is very common (range, 15–52%) in patients with esophageal atresia. Children present with a wide range of symptoms. The most common diagnostic tools to evaluate esophageal dysphagia, such as upper barium study and manometry, aim to characterize anatomy and function of the esophageal body and the esophagogastric junction (EGJ). Using these technologies, a variety of pathological motor patterns have been identified in children with esophageal atresia. However, the most challenging part of diagnosing patients with esophageal dysphagia lies in the fact that these methods fail to link functional symptoms such as dysphagia with the esophageal motor disorders observed. A recent method, called pressure-flow analysis (PFA), uses simultaneously acquired impedance and manometry measurements, and applies an integrated analysis of these recordings to derive quantitative pressure-flow metrics. These pressure-flow metrics allow detection of the interplay between bolus flow, motor patterns, and symptomatology by combining data on bolus transit and bolus flow resistance. Based on a dichotomous categorization, flow resistance at the EGJ and ineffective esophageal bolus transit can be determined. This method has the potential to guide therapeutic decisions for esophageal dysmotility in pediatric patients with esophageal atresia

Neonates and medicines: a roadmap to further improve neonatal pharmaceutical care

The treatment of newborns with safe and effective medicines is of critical importance for their outcome and subsequent quality of life. Despite this, it is still a common practice to prescribe medicines to neonates outside the label, extrapolating from dosing regimens and indications validated in older populations and based on non-neonatal pathophysiology. In a recent meta-analysis (2015) evaluating 829 (1994–2012) studies on prescribing practices in pediatric hospital care, off-label and unlicensed medicines prescriptions ranged from 12 to 71 % and 0.2 to 48 %. These authors hereby reconfirmed that (pre)term neonates were still most commonly exposed to off-label and unlicensed medicines [12]

Physiology-based IVIVE predictions of tramadol from in vitro metabolism data

To predict the tramadol in vivo pharmacokinetics in adults by using in vitro metabolism data and an in vitro-in vivo extrapolation (IVIVE)-linked physiologically-based pharmacokinetic (PBPK) modeling and simulation approach (SimcypA (R)). Tramadol metabolism data was gathered using metabolite formation in human liver microsomes (HLM) and recombinant enzyme systems (rCYP). Hepatic intrinsic clearance (CLint(H)) was (i) estimated from HLM corrected for specific CYP450 contributions from a chemical inhibition assay (model 1); (ii) obtained in rCYP and corrected for specific CYP450 contributions by study-specific intersystem extrapolation factor (ISEF) values (model 2); and (iii) scaled back from in vivo observed clearance values (model 3). The model-predicted clearances of these three models were evaluated against observed clearance values in terms of relative difference of their geometric means, the fold difference of their coefficients of variation, and relative CYP2D6 contribution. Model 1 underpredicted, while model 2 overpredicted the total tramadol clearance by -27 and +22%, respectively. The CYP2D6 contribution was underestimated in both models 1 and 2. Also, the variability on the clearance of those models was slightly underpredicted. Additionally, blood-to-plasma ratio and hepatic uptake factor were identified as most influential factors in the prediction of the hepatic clearance using a sensitivity analysis. IVIVE-PBPK proved to be a useful tool in combining tramadol's low turnover in vitro metabolism data with system-specific physiological information to come up with reliable PK predictions in adults

All medicines have side effects

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Dose rationale and pharmacokinetics of dexmedetomidine in mechanically ventilated new-borns : impact of design optimisation

Purpose: There is a need for alternative analgosedatives such as dexmedetomidine in neonates. Given the ethical and practical difficulties, protocol design for clinical trials in neonates should be carefully considered before implementation. Our objective was to identify a protocol design suitable for subsequent evaluation of the dosing requirements for dexmedetomidine in mechanically ventilated neonates. Methods: A published paediatric pharmacokinetic model was used to derive the dosing regimen for dexmedetomidine in a first-in-neonate study. Optimality criteria were applied to optimise the blood sampling schedule. The impact of sampling schedule optimisation on model parameter estimation was assessed by simulation and re-estimation procedures for different simulation scenarios. The optimised schedule was then implemented in a neonatal pilot study. Results: Parameter estimates were more precise and similarly accurate in the optimised scenarios, as compared to empirical sampling (normalised root mean square error: 1673.1% vs. 13,229.4% and relative error: 46.4% vs. 9.1%). Most importantly, protocol deviations from the optimal design still allowed reasonable parameter estimation. Data analysis from the pilot group (n = 6) confirmed the adequacy of the optimised trial protocol. Dexmedetomidine pharmacokinetics in term neonates was scaled using allometry and maturation, but results showed a 20% higher clearance in this population compared to initial estimates obtained by extrapolation from a slightly older paediatric population. Clearance for a typical neonate, with a post-menstrual age (PMA) of 40 weeks and weight 3.4 kg, was 2.92 L/h. Extension of the study with 11 additional subjects showed a further increased clearance in pre-term subjects with lower PMA. Conclusions: The use of optimal design in conjunction with simulation scenarios improved the accuracy and precision of the estimates of the parameters of interest, taking into account protocol deviations, which are often unavoidable in this event-prone population