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Objectives Although amiodarone is an effective treatment for severe paediatric arrhythmias, uncertainties about adverse effects such as hypotension, bradycardia and excessive serum drug concentrations persist. Therefore, the aims of this study were to: (a) determine serum concentrations of intravenous (IV) amiodarone following a widely implemented dosing regimen of 5 mg/kg bolus plus a 10 mg/kg/day continuous infusion and (b) generate descriptive data on safety parameters such as hypotension, bradycardia or corrected QT (QTc) prolongation during this regimen. Design Prospective observational study. Setting Paediatric intensive care unit. Patients Twenty paediatric patients (median age, 0.23 years; range, 6 days-15.04 years) with arrhythmia secondary to or without cardiac surgery. Interventions None. Interventions None. Results Amiodarone serum concentrations increased markedly during bolus, followed by rapid decreases during maintenance infusion. All patients had serum concentrations regarded as effective in adults (median concentration range: 1.30-2.06 mM/L during maintenance phase). Amiodarone suppressed arrhythmias in 18 (90%) patients. Mean QTc intervals for pretherapy, during and post-therapy periods were 443 ms, 458 ms and 467 ms, respectively. Eight patients had hypotension. Conclusions Amiodarone was effective in the majority of children in this small cohort. [ABSTRACT FROM AUTHOR]

Abstract: Phenylketonuria (PKU), an autosomal recessive disease with phenylalanine hydroxylase (PAH) deficiency, was recently shown to be a protein misfolding disease with loss-of-function. It can be treated by oral application of the natural PAH cofactor tetrahydrobiopterin (BH4) that acts as a pharmacological chaperone and rescues enzyme function in vivo. Here we identified Pah enu1/2 bearing a mild and a severe mutation (V106A/F363S) as a new mouse model for compound heterozygous mild PKU. Although BH4 treatment has become established in clinical routine, there is substantial lack of knowledge with regard to BH4 pharmacodynamics and the effect of the genotype on the response to treatment with the natural cofactor. To address these questions we applied an elaborate methodological setup analyzing: (i) blood phenylalanine elimination, (ii) blood phenylalanine/tyrosine ratios, and (iii) kinetics of in vivo phenylalanine oxidation using 13C-phenylalanine breath tests. We compared pharmacodynamics in wild-type, Pah enu1/1 , and Pah enu1/2 mice and observed crucial differences in terms of effect size as well as effect kinetics and dose response. Results from in vivo experiments were substantiated in vitro after overexpression of wild-type, V106A, and F263S in COS-7 cells. Pharmacokinetics did not differ between Pah enu1/1 and Pah enu1/2 indicating that the differences in pharmacodynamics were not induced by divergent pharmacokinetic behavior of BH4. In conclusion, our findings show a significant impact of the genotype on the response to BH4 in PAH deficient mice. This may lead to important consequences concerning the diagnostic and therapeutic management of patients with PAH deficiency underscoring the need for individualized procedures addressing pharmacodynamic aspects. [ABSTRACT FROM AUTHOR]

Background : Pediatric trials to add missing data for evidence-based pharmacotherapy are still scarce. A tailored training concept appears to be a promising tool to cope with critical and complex situations before enrolling the very first patient and subsequently to ensure high-quality study conduct. The aim was to facilitate study success by optimizing the preparedness of the study staff shift. Method: An interdisciplinary faculty developed a simulation training focusing on the communication within the informed consent procedure and the conduct of the complex pharmacokinetic/pharmacodynamic (PK/PD) sampling within a simulation facility. Scenarios were video-debriefed by an audio-video system and manikins with artificial blood simulating patients were used. The training was evaluated by participants' self-assessment before and during trial recruitment. Results: The simulation training identified different optimization potentials for improved informed consent process and study conduct. It facilitated the reduction of avoidable errors, especially in the early phase of a clinical study. The knowledge gained through the intervention was used to train the study teams, improve the team composition and optimize the on-ward setting for the FP-7 funded "LENA" project (grant agreement no. 602295). Self-perceived ability to communicate core elements of the trial as well as its correct performance of sample preparation increased significantly (mean, 95% CI, p ≤ 0.0001) from 3 (2.5–3.5) to four points (4.0–4.5), and from 2 (1.5–2.5) to five points (4.0–5.0). Conclusion: An innovative training concept to optimize the informed consent process and study conduct was successfully developed and enabled high-quality conduct of the pediatric trials as of the very first patient visit. [ABSTRACT FROM AUTHOR]

• Pharmacokinetic data are too limited to support an age-related effect on enalapril • Moderate strong evidence supports enalapril's efficacy in older hypertensive children. • Moderate-level evidence supports the use of enalapril to reduce proteinuria. • A major information gap remains on the pharmacokinetics and pharmacodynamics of enalapril in children. Enalapril is an angiotensin-converting enzyme (ACE) inhibitor that is used for the treatment of (paediatric) hypertension, heart failure and chronic kidney diseases. Because its disposition, efficacy and safety differs across the paediatric continuum, data from adults cannot be automatically extrapolated to children. This review highlights paediatric enalapril pharmacokinetic data and demonstrates that these are inadequate to support with certainty an age-related effect on enalapril/enalaprilat pharmacokinetics. In addition, our review shows that evidence to support effective and safe prescribing of enalapril in children is limited, especially in young children and heart failure patients; studies in these groups are either absent or show conflicting results. We provide explanations for observed differences between age groups and indications, and describe areas for future research. [ABSTRACT FROM AUTHOR]