bluuebunny/crossref_metadata_2025_split huggingface dataset:
P86 Treatment modalities in peripheral facial nerve palsy in children and adolescents
Authors: Samardzic J , Kukolj B , Jovanovic M , Djuric O , Jancic J 
Published: May 2019

BackgroundBell´s palsy is the most common type of peripheral facial palsy in pediatrics. Recent studies strongly support the combined therapy with corticosteroids (CS), antiviral drugs and vitamins B. Our study aims to assess the effectiveness of proposed therapeutic modalities, including the relation between the patients‘ recovery and their age, etiological factors and applied treatment.MethodsThe retrospective analysis involved 88 patients (52 females/36 males), between 18 months and 18 years old; the average age was 11.7 years. Data was obtained from the documentation of patients hospitalized at the Clinic of Neurology and Psychiatry for Children and Youth in Belgrade, from 2000 to 2017. House Brackmann´s scale was used for the assessment of disease course and outcome. Pearson´s χ2 test, Friedman´s test and general linear model were applied for statistical data processing.ResultsThe majority of patients were treated with combined CS/vitamins (42.0%) and CS/antiviral/vitamins (17.0%), whereas CS only received 22.7% of patients, all with an appropriate physical treatment. The group of idiopathic paralysis makes 62.5%, while the incidence of symptomatic paralysis is 37.5%; however, the recovery rate between these groups has not been shown (p=0.309). Patients received CS therapy were divided into 4 groups: CS only, CS+antiviral, CS+vitamins B, and CS+antiviral+vitamins B. The statistically significant recovery was registered in each group (p< 0.001); however, no difference was found between the groups in term of recovery rate (p=865). For the assessment of recovery period in relation to the age, the obtained p value was 0.054, a borderline level, suggesting a faster recovery of children at younger age.ConclusionThe acute one-sided mimic musculature weakness is mostly idiopathic. The effectiveness of the CS therapy was strongly supported, suggesting CS as a core treatment for the Bell´s palsy. It has been shown the faster recovery of children at younger age.Disclosure(s)Nothing to disclose
P94 Reliable acquisition of plasma renin activity in the maturating renin-angiotensin-aldosterone-system by a validated small-volume assay in context of the LENA project
Authors: Suessenbach FK , Feickert M , Tins J , Burckhardt BB 
Published: May 2019

BackgroundPhysiological and pathophysiological circumstances of the paediatric renin-angiotensin-aldosterone-system (RAAS) are still inadequately understood. Due to the limited paediatric data available, the LENA (Labeling of Enalapril from Neonates up to Adolescents) project aimed to comprehensively investigate the drug enalapril and its effect on humoral parameters of the RAAS. Examination of four humoral parameters, including plasma renin activity (PRA), was conducted regarding cardiac diseased paediatric population receiving enalapril, of which 60% were below 1 year of age. To fully address the agreed Paediatric Investigation Plan (EMEA-001706-PIP) of the LENA project, reliable small-volume assays for pharmacodynamics determination were mandatory to ensure the reliable data sets.Materials and methodsA commercial PRA enzyme linked immunosorbent assay (ELISA) was tailored for paediatric application and validated according to European Medicine Agency (EMA) and U.S. Food and Drug Administration (FDA) bioanalytical guidelines.1 2 In this context, accuracy, precision, total error, linearity, parallelism, matrix effects and stability were investigated.ResultsThe adopted bioanalytical PRA-assay was successfully validated. Between-run precision (CV) and accuracy (relative error) ranged from 1.6% to 19.6% and -13.0% to +11.2% respectively. Samples of five different human sources showed no substantial matrix effect and facilitated the assay’s application to heterogeneous populations. The obtained precision of parallelism of five dilution steps ranged from 7.7% to 8.3% allowing to dilute high samples within the calibration range. Stability measurements proved four freeze and thaw cycles plus short-term and long-term (37 weeks) stability. Overall, all results were complied with guideline requirements.ConclusionThe FDA/EMA-compliant PRA assay is able to accurately and precisely quantify PRA values in 50 µL plasma and is applicable for GCLP-compliant clinical studies enabling sophisticated investigations in children within the LENA project.ReferencesCommittee for Medicinal Products for Human Use (CHMP): EMEA/CHMP/EWP/192217/2009 Rev. 1 Corr. 2** Guideline on bioanalytical method validation, June, 2015U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Veterinary Medicine (CVM): Bioanalytical Method Validation Guidance for Industry, May 2018Disclosure(s)Fabian K. Suessenbach, Martin Feickert, Jutta Tins and Bjoern B. Burckhardt declare that there is no conflict of interest. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA).
P98 Semi-quantification and localization of membrane transporters in paediatric kidney tissue
Authors: van Borselen M , van Groen B , Pertijs J , Wilmer M , Smeets B , Verdijk R , de Wildt S 
Published: May 2019

BackgroundThe kidney has a critical role in disposition, efficacy and toxicity of drugs and xenobiotics. Developmental changes of renal membrane transporters have the potential to explain population variability in paediatric pharmacokinetics and -dynamics of drugs but data are missing. We aimed to further delineate the expression of human renal tubular transporters multidrug resistance-associated protein (MRP) 4 and MRP2 and study localization in paediatric kidney samples.MethodsWe planned to semi-quantify expression levels and to study the age-specific localization of the transporters MRP4 and MRP2 with immunohistochemistry on 44 human neonatal and paediatric kidney samples with age range of 24,00 - 40,00 weeks gestational age (GA) and 0,29 - 744 weeks post-natal age (PNA). The staining intensity was semi-quantitatively scored by two independent observers (MB and BG).ResultsMRP4 is found to be localized at the apical membrane of the renal proximal tubules at 27 weeks of GA (n=3, 1,29- 4 weeks PNA) and no age-related changes of expression levels were detected. In a premature neonate of 24 weeks GA (n=1), no MRP4 was detected. The MRP2 staining did not meet the requirements to be scored and was rejected.ConclusionMRP4 is expressed from at least 27 weeks GA onwards and does not show developmental changes. The localization was similar as in adults (Ritter et al., 2005). The half-life of the MRP4 substrate furosemide was found to be 6 to 20-fold longer in neonates than in adults (Pacifici, G.M., 2013). This could potentially be linked with the absence of MRP4 in a premature neonate with GA 24 weeks. However, these data should be confirmed as we only had 1 sample of ±24 weeks GA available. Moreover, our data help us in understanding altered disposition of transporter substrates in paediatrics.ReferencesPacifici, G. M. ( 2013). Clinical pharmacology of furosemide in neonates: a review. Pharmaceuticals;6(9):1094–1129.Ritter CA, Jedlitschky G, Meyer zu Schwabedissen H, Grube M, Köck K, & Kroemer HK. ( 2005). Cellular export of drugs and signaling molecules by the ATP-binding cassette transporters MRP4 (ABCC4) and MRP5 (ABCC5). Drug metabolism reviews;37(1):253–278.Disclosure(s)Nothing to disclose
P102 Alternative splicing of the SLCO1B1 transporter in paediatric liver
Authors: van Groen BD , Bi C , Gaedigk R , Staggs V , Tibboel D , de Wildt SN , Leeder JS 
Published: May 2019

BackgroundAlternative mRNA transcripts occur in >90% of human genes and may be triggered by developmental signals. The hepatic transporter OATP1B1 (gene name SLCO1B1) traffics substrates across the hepatic membrane, and shows age-related changes in protein expression. We aimed to predict novel isoforms of OATP1B1 by studying alternative splicing of SLCO1B1 in human paediatric post-mortem liver tissue, and the relationship of their mRNA expression with age.Methods mRNA expression of SLCO1B1 transcripts was determined using RNA sequencing (HISAT2/StringTie). Novel mRNA transcripts were considered of relevance when (1) the expression was >5% of the annotated isoform, (2) it was a SLCO1B7 and SCLO1B1 hybrid transcript, or (3) when the expression was associated with age. The software packages ORF-finder, TMpred and TOPO2 were used to predict the protein sequence and structure of the novel isoforms. Relationship of expression with age was studied with the Kruskal-Wallis test for age groups (fetal, 0–1.5 year, 1.5–6 year, 6–12 year and 12–18 year) and with Spearman correlation tests for age on continuous scale.ResultsIn 97 hepatic post-mortem tissues (gestational age median 16.4 [range 14.7–41.3] weeks, postnatal age 0.36 [0 - 17] years) 27 novel mRNA transcripts were detected. Of these, 13 were relevant: 2 isoforms are predicted to translate into amino acid sequences similar to the annotated isoform for OATP1B1, 9 isoforms may translate into truncated versions, and the expression of 8 isoforms was associated with age. None of the isoforms had an ORF that covered the SLCO1B7 region.ConclusionWe showed that novel SLCO1B1 mRNA isoforms potentially translate into OATP1B1 protein with unknown function, and that alternative splicing may well be a regulatory mechanism for SLCO1B1 expression during development. This data provides a better understanding of age-related changes in the expression of OATP1B1, and, with that, potentially improves prediction of disposition of endogenous and exogenous substrates.Disclosure(s)BG was supported, in part, by the Ter Meulen fund 2018 provided by the Royal Dutch Academy of Sciences. The National Institute of Child Health and Human Development Brain and Tissue Bank for Developmental Disorders at the University of Maryland is funded by the National Institutes of Health (NIH) contract HHSN275200900011C, reference number, N01-HD-9-0011 and the Liver Tissue Cell Distribution System is funded by NIH contract number N01-DK-7-0004/HHSN267200700004C.
P103 Target attainment of amikacin therapy in critically ill children
Authors: Verbruggen J , Jakipbayeva K , Van Der Heggen T , Dhont E , Dhondt L , Vande Walle J , De Paepe P , Herck I , De Cock P 
Published: May 2019

BackgroundResearch regarding the optimal amikacin (AMI) dosing regimen in critically ill children is scarce.1 Optimal AMI efficacy has been observed with plasma peak over minimal inhibitory concentration of the suspected pathogen (peak/MIC) ratios of 8 to 10. Plasma trough levels (Cmin) >5mcg/ml are related to its toxicity.The objectives of this pilot study were to: (1) evaluate target attainment rate and occurrence of supratherapeutic concentrations in early and assumed steady-state dose conditions, and (2) investigate the correlation between AMI clearance and estimated glomerular filtration (eGFR).MethodsChildren admitted to the ICU receiving intravenous AMI (20 mg/kg once daily) were included. Serial blood samples were obtained from early (1st/2nd) and assumed steady-state (SS) doses. The evaluated target peak concentration range was 54–64 mcg/ml, assuming a Pseudomonas aeruginosa infection with Eucast MIC breakpoint of 8 mg/L, and a Cmin threshold of 5 mcg/L. eGFR was estimated using the modified Schwartz formula. AMI clearance was calculated using noncompartmental PK analysis. Correlation was assessed by means of a scatter plot and Pearson Correlation Coefficient (r).ResultsTwenty-one patients (median age1,5 years; range:0,5 months-14 year, median eGFR 162 ml/min/1,73m2 (range:107–475 ml/min/1,73m2) were included. In early dose conditions, 69% of patients had therapeutic peak concentrations (median: 60 mcg/ml; range:26–73 mcg/ml). In SS conditions, 60% of patients had therapeutic peak concentrations (median: 59 mcg/ml; range:35–83 mcg/ml). Only one supratherapeutic Cmin was observed. AMI clearance (median 0.08L/h/kg; range: 0.05–0.91 L/h/kg) was comparable to what has been previously reported but showed no correlation with eGFR (r=0.1; p=0,66) [1].ConclusionThis pilot study suggest that the current AMI dosing regimen may lead to subtherapeutic concentrations in patients infected with less susceptible pathogens. Supratherapeutic Cmin were far less of a concern. Dose adjustments of renally cleared drugs based on eGFR may not be reliable in this patient population.ReferencesIllamola SM, Sherwin CM, van Hasselt JGC. Clinical Pharmacokinetics of Amikacin in Pediatric Patients: A Comprehensive review of Population Pharmacokinetic Analysis. Clin Pharmacokinet ( 2018) 57:1217.Disclosure(s)Nothing to disclose
P110 Population pharmacokinetics and dosing optimisation of imipenem in children with haematological malignancie
Authors: Dong L , Zhai X-Y , Yang Y-L , Wang L , Zhou Y , Shi H-Y , Tang B-H , Y-E Wu , Yang F , Wen L , Kong H-X , Zhi L-J , Jacqz-Aigrain E , Zhao W 
Published: May 2019

BackgroundImipenem/cilastatin is widely used for the treatment of children with serious infections. Currently, there is lack of pharmacokinetic studies of imipenem in children with hematological malignancies. Given the significant impact of disease on pharmacokinetics and increased resistance, we aimed to conduct a population based pharmacokinetic study of imipenem and optimize the dosage regimens for this vulnerable population.MethodsAfter treated with IMP/CS, blood samples of children were collected and the concentration of imipenem were quantified using HPLC-UV. Then, population level pharmacokinetic analysis was conducted using NONMEM software.ResultsData from 56 children (age range: 2.03–11.82 years) with haematological malignancies were collected to conduct a population based pharmacokinetic analysis. In this study, a two-compartment model that followed first-order elimination was found to be best suitable. The parameters of current weight, age and creatinine elimination rate were significant covariates that influenced imipenem pharmacokinetics. As a result, 52.0%, 65.2% and 76.6% of children reached the pharmacodynamic target (70% fT>MIC) against sensitive pathogens with an MIC of 0.5 mg/L at 15, 20 and 25 mg/kg q6h of imipenem, respectively. However, only 17.2% of children achieved the pharmacodynamic target against Pseudomonas aeruginosa with an MIC of 2 mg/L at a dose of 25 mg/kg q6h.ConclusionPopulation pharmacokinetics of imipenem was assessed in children. The current dosage regimens of imipenem are underdose for resistant pathogens including Pseudomonas aeruginosa and Acinetobacter baumannii. However, for sensitive pathogens, imipenem has an acceptable pharmacodynamic target rate at a dosage of 25 mg/kg q6h.Disclosure(s)Nothing to disclose.
O15 Lidocaine plasma concentrations and anti-epileptic efficacy in term and preterm neonates: prospective validation of a new dosing regimen
Authors: Favié L , Rademaker C , van den Broek M , Egberts T , van Bel F , Groenendaal F 
Published: May 2019

BackgroundLidocaine is used as an add-on anti-epileptic drug (AED) in neonates when seizures persist despite treatment with first line anticonvulsants. Although lidocaine has shown to be an effective anticonvulsant, cardiac toxicity associated with plasma concentrations >9 mg/L have limited its wide scale use.1 Previous studies from our group have proposed a dosing regimen for effective and safe lidocaine use in term and preterm neonates with plasma concentrations not exceeding 9 mg/L.2,3AimThe present study evaluated lidocaine use as anticonvulsant in neonates and prospectively validated the new dosing regimen.MethodsData were collected at the neonatal intensive care unit of the University Medical Centre Utrecht. Neonates refractory to at least one AED received lidocaine according to clinical protocol. Lidocaine was administered as a 2 mg/kg loading dose in 10 minutes followed by a three stage maintenance phase with tapering lidocaine doses. Lidocaine plasma concentrations were measured from blood samples taken at the end of the first stage (highest lidocaine dose) and during the second or third stage (tapered lidocaine dose). Efficacy was determined as abolishment of seizures during lidocaine therapy and no recurrence within 24 h after cessation.ResultsLidocaine data were available from 75 neonates (gestational age 36.2 weeks [range 25.0–42.4, < 36.0 38.7%], birth weight 2771 g [range 675–4875], male 64.0%, mortality 45.3%). 23 patients (30.7%) received the new dosing regimen, 52 patients (60.7%) the old regimen. Highest measured plasma concentration with the new regimen was 9.15 mg/L and 16.8 mg/L with the old regimen. Efficacy with the new regimen was 56.5% and 53.8% for the old regimen. No cardiac toxicity was observed in either group.ConclusionsThe new lidocaine dosing regimen leads to safe and effective lidocaine plasma concentrations and has similar efficacy compared to the previous dosing regimen.ReferencesWeeke LC, Toet MC, Van Rooij LGM, Groenendaal F, Boylan GB, Pressler RM, et al. Lidocaine response rate in aEEG-confirmed neonatal seizures: Retrospective study of 413 full-term and preterm infants 2015;233–42.Van den Broek MPH, Rademaker CMA, van Straaten HLM, Huitema ADR, Toet MC, de Vries LS, et al. Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: efficacy, safety and dosing. Arch Dis Child Fetal Neonatal Ed 2013;98(4):F341–5.Van Den Broek MPH, Huitema a. DR, Van Hasselt JGC, Groenendaal F, Toet MC, Egberts TCG, et al. Lidocaine (lignocaine) dosing regimen based upon a population pharmacokinetic model for preterm and term neonates with seizures. Clin Pharmacokinet 2011;50(7):461–9.Disclosure(s)Nothing to disclose
P113 Population pharmacokinetics and dosing optimization of azlocillin in neonates
Authors: Zhao W , Group TINN-Global Study 
Published: May 2019

BackgroundAzlocillin is prescribed for the treatment of infections in neonatal clinical practice, however, the optimized dose is still questionable due to the lack of pharmacokinetic study Thus, we aim to evaluate the population pharmacokinetics of azlocillin and optimize dosing regimen in order to improve azlocillin treatment in neonates.MethodsThis is a prospective, open label pharmacokinetic study of azlocillin. Blood samples were collected using an opportunistic sampling design. Theplasma concentrations ofazlocillinwere determined by high performance liquid chromatography method with UV detection. Population pharmacokinetic-pharmacodynamic analysis was performed using NONMEM software.ResultsNinety-five neonates (postmenstrual age (PMA) range 32.1–42.0 weeks) were included in this study. A total of 167 azlocillin concentrations were available for the final analysis. A one-compartment model with first-order elimination best fitted the data. Covariate analysis demonstrated that current weight, birth weight and postnatal age had significant effect on azlocillin pharmacokinetics. MonteCarlo simulation demonstrated that for the common pathogens with MIC of 8 mg/liter, the currently used dosage regimen (100 mg/kg, q12h) resulted in 61.2% of newborns achieved the pharmacodynamic target (drug concentrations above MIC during 70% of the dosing interval) with a potential risk of underdosing. When shortening the dosing interval to 8 hours, the target could be achieved in 89.3% of patients, using the MIC break point of 8 mg/liter.ConclusionThe population pharmacokinetics characteristics of azlocillin were assessed in neonates. An optimal dosage regimen of azlocillin was established based on developmental pharmacokinetics-pharmacodynamics in this vulnerable population.Disclosure(s)Nothing to disclose.
P115 Effects of the clinical pharmacist’s intervention on rationality of parenteral nutrition
Authors: Zhu M , Xu J 
Published: May 2019

ObjectiveThrough STRONGkids1 2 (screening tool risk on nutritional status and growth of children) to observe the influences on nutritional indicators and postoperative recovery of different nutritional risk levels of children with intussusception in the use of parenteral nutrition support. Through educating and interventing the doctors to promote the use of parenteral nutrition more reasonable and the hospitalization costs lower.3MethodsChildren were grouped according to different scores of STRONGkids,4 5 and each group was divided into two groups A and B according to using parenteral nutrition only or no nutrition support at all. The proportion of the two groups, nutritional indicators and postoperative recovery of the children after surgery were compared to observe the parenteral nutrition usage rate of different groups, and the use of parenteral nutrition was necessary or not. The clinical pharmacist intervened the doctors according to the research results. 1 year later, the indicators above were compared again.ResultsThere were no significant differences on nutritional indicators and postoperative recovery in 1–2 score groups between group A and B, but the hospitalization cost in group A was significantly higher than that in group B. In 3-score group of children, the decreases of weight, prealbumin and retinol binding protein were more significant in group B than in group A, and the hospitalization days of group A were significantly shorter than group B. The incidence of adverse reactions of using parenteral nutrition was significantly higher. According to above results, the clinical pharmacist instructed doctors to improve the indication of parenteral nutrition according to the relevant guidelines.1 year later, the usage rate of parenteral nutrition dropped in 1–2 score groups. The incidence of adverse reactions and the costs of hospitalization were significantly decreased.ConclusionsThe clinical pharmacist played an important role in promoting the rational use of parenteral nutrition.6 7ReferencesTeixeira AF, Viana KD.Nutritional screening in hospitalized pediatric patients: a systematic review.[J]J Pediatr (Rio J) 2016, 92(4):343–352.Forga L, Bolado F, Goñi MJ,et al. Low serum levels of prealbumin, retinol binding protein, and retinol are frequent in adult type 1 diabetic patients.J Diabetes Res2016; 2016:2532108. doi: 10.1155/2016/2532108. Epub 2016 Nov 29.Pediatric Collaborative Group, Society of Parenteraland Enteral Nutrition. Guidelines for pediatric clinical application of enteral and parenteral nutritional support in China[J]. Zhonghua Er Ke Za Zhi, 2010, 48(6):436–441.Abunnaja S, Cuviello A, Sanchez JA.Enteralandparenteral nutritionin the perioperative period: state of the art[J].Nutrients. 2013, 5(2):608–623.Yi F, Ge L, Zhao J, Lei Y,et al.Meta-analysis:total parenteral nutritionversustotalenteral nutritionin predicted severe acute pancreatitis[J].Intern Med. 2012, 51(6):523–530.Disclosure(s)Nothing to disclose.