bluuebunny/crossref_metadata_2025 huggingface dataset:
Electronic devices and myopic refraction among children aged 6‐14 years in urban areas of Tianjin, China
Authors: Liu Shengxin , Ye Sheng , Xi Wei , Zhang Xin
Published: May 2019

Purpose

To assess associations between different types of electronic devices, myopic refraction and ocular biometric parameters in children aged 6–14 years in urban areas of Tianjin, China.

Methods

A school‐based, cross‐sectional study was performed on 566 children (302 boys and 264 girls). The children underwent a comprehensive eye examination, including cycloplegic autorefraction and ocular biometry. The children's parents completed a detailed questionnaire that included each child's demographics, the use of electronic devices and other related risk factors.

Results

Myopia was not associated with time spent using various electronic devices. However, the mean spherical equivalent refraction (SER) decreased by 0.28 D (p = 0.042) and 0.33 D (p = 0.018) for each 1‐h increase in the time spent using smart phones and computers, respectively. In the multiple linear regression analyses of factors associated with theSER, the standardised coefficient B for time spent reading and writing was approximately four to five times larger than the standardised coefficient for time spent using smart phones or computers. Time spent using tablets and watching television was not significantly associated with theSER. A longer axial length (AL) was associated with more time spent using smart phones (B = 0.23,p = 0.006) and computers (B = 0.26,p = 0.002) but not using tablets (p = 0.45) and watching television (p = 0.45). No significant association was found between other ocular biometric parameters and time spent using various electronic devices.

Conclusions

On average, a more myopicSERand longerALwere both associated with more time spent using smart phones and computers, but not with time spent using tablets and watching television. The magnitude of the association betweenSERand time spent reading and writing was a substantially larger than that for smart phone or computer use. Different types of electronic devices had differing levels of association with myopic refraction.
Colorectal tumor-on-a-chip system: A 3D tool for precision onco-nanomedicine
Authors: Carvalho M. R. , Barata D. , Teixeira L. M. , Giselbrecht S. , Reis R. L. , Oliveira J. M. , Truckenmüller R. , Habibovic P.
Published: May 2019

This colorectal tumor-on-chip model is an original and reliable platform for high-throughput drug screening and genetic expression.
Cancer-associated mutation and beyond: The emerging biology of isocitrate dehydrogenases in human disease
Authors: Tommasini-Ghelfi Serena , Murnan Kevin , Kouri Fotini M. , Mahajan Akanksha S. , May Jasmine L. , Stegh Alexander H.
Published: May 2019

We review the contribution of altered isocitrate dehydrogenase activity to the pathogenesis of a broad spectrum of human disease.
ARID1A spatially partitions interphase chromosomes
Authors: Wu Shuai , Fatkhutdinov Nail , Rosin Leah , Luppino Jennifer M. , Iwasaki Osamu , Tanizawa Hideki , Tang Hsin-Yao , Kossenkov Andrew V. , Gardini Alessandro , Noma Ken-ichi , Speicher David W. , Joyce Eric F. , Zhang Rugang
Published: May 2019

ARID1A is important for genome folding, spatial partitioning of interphase chromosomes, and intermixing of small chromosomes.
Framework to help design and review research involving children
Authors: Phillips Bob , Davies Hugh T , Preston Jennifer , Stones Simon R
Published: May 2019

This is the third of a series of four articles addressing ethical approaches and issues in undertaking clinical research with children and young people (CYP). This paper addresses the major ethical aspects of studies with CYP, where they vary from studies in adults.
P69 Pharmacokinetics of a continuous infusion of piperacillin/tazobactam to children using an elastomeric pump (POPPET Study): pilot data from double lumen central lines
Authors: Moss J , Price V , Paulus S , Ramos-Martin V , Melaine A , Evans E , Newland P , Hope W , Hawcutt D , Pizer B
Published: May 2019

Background

Piperacillin/Tazobactam is the first-line antibiotic for the treatment of febrile neutropenia in the UK. There is increasing interest in administration by continuous infusion in adult studies, but paediatric data is lacking. A continuous infusion, if given via an elastomeric pump could also facilitate earlier discharge from hospital.

Methods

Children with an oncology/haematology diagnosis admitted to Alder Hey Children’s Hospital with febrile neutropenia, normally treated with Piperacillin/Tazobactam via elastomeric device were considered eligible for the study. Patients received 24–36 hours of intermittent dosing before continuous dosing commenced via elastomeric pump. We analysed the data from 5 patients with double lumen central lines as a pilot phase to determine if expanded recruitment to include patients with single lumen lines was possible.

Results

Five patients were recruited, four of which had the continuous infusion. The mean Cmax following intermittent dosing of piperacillin and tazobactam from the lumen used for drug administration were 189.7 mg/L, 95% CI [71.7 - 307.9] and 18.5 mg/L, 95% CI [10.7, 26.3] respectively. The mean Cmax following intermittent dosing for the ‘empty’ lumen were 160.5 mg/L, 95% CI [121.6 - 199.4] for piperacillin and 13.7 mg/L, 95% CI [11.2 - 16.3] for tazobactam. The largest difference seen was on patient 002 with a concentration of piperacillin almost double that seen in the ‘empty’ lumen (429 mg/L vs 233 mg/L).

Conclusion

The lumen used for drug administration has enough residual drug to influence the results, so expanding recruitment to include single lumen lines is not going to be undertaken. The study has been amended to recognise this, and recruitment will continue with double lumen central lines only.

Disclosure(s)

Nothing to disclose
O11 Characterising the pharmacokinetics of phenobarbitone in neonates to facilitate future individualised dosing
Authors: Williams A , Donovan T , Charles B , Staatz C
Published: May 2019

Background

Phenobarbitone is commonly used as a first-line drug in the treatment of neonatal seizures. Previous studies, with small subject numbers, have identified covariates that may influence the pharmacokinetics of phenobarbitone but results have been inconsistent. In particular, oral bioavailability is poorly described with doses reported as being identical for intravenous and oral administration, however, 2 recent studies have reported oral bioavailability of 49% and 59% respectively.1,2

Methods

A population pharmacokinetic model was built based on routine therapeutic drug monitoring data from 112 infants at the Royal Brisbane and Women’s Hospital Neonatal Intensive Care Unit. Population modelling was performed using NONMEM 7.3 and PsN 4.7 with assistance from R studio and the packages Xpose and VPC. Body weight with allometric scaling on Clearance (CL) and Volume of Distribution (V) were included a priori in the structural model. Covariates tested included age (post-menstrual, gestational and post-natal), Apgar scores, concomitant phenytoin treatment, infection and method of nutrition.

Results

A one-compartment model provided an adequate fit to the data. Typical clearance increased with patient post-natal age (PNA) and was best modelled using the equation CL = 5.1 *WT0.75 * (PNA/6.25)0.43 (mL/h) were weight is in kg, PNA in days and 6.25 is the median post-natal age. Volume of distribution (V) was best modelled using the equation V = 799 * WT1.0 (mL). Oral bioavailability (F) was 85%. Between-subject variability was 25% and 30% respectively for CL and V.

Conclusion

This study describes the largest population pharmacokinetic model of phenobarbitone developed to date with estimates of CL and V similar to previously published models. Estimated F is higher than previously reported but still lower than the implied F of 100% in most recommended dosing regimens. The model could be used to assist with future individualisation of dosing in this cohort.

References

Marsot A, et al. Pharmacokinetics and absolute bioavailability of phenobarbital in neonates and young infants, a population pharmacokinetic modelling approach. Fundam Clin Pharmacol 2014;28(4):465–71.

Voller S, et al. Model-based clinical dose optimization for phenobarbital in neonates: An illustration of the importance of data sharing and external validation. Eur J Pharm Sci 2017;109s:S90–S97.

Disclosure(s)

Nothing to disclose
P75 Relation between polymorphism of folic acid cycle genes and effectiveness of methotrexate in children with juvenile idiopathic arthritis
Authors: Panko N
Published: May 2019

Background

Methotrexate (MTX) is the basic treatment of patient with Juvenile Idiopathic Arthritis (JIA), but effectiveness of this therapy is different. We aimed to study effectiveness of MTX in children with JIA with different genotypes of folic acid cycle genes.

Methods

The study included 8 patients with JIA. For determination of MTX effectiveness the American College of Rheumatology pediatric criteria (ACR-pedi) was used. Patients were divided into 2 groups according the effectiveness of MTX treatment. Group I included 4 patients, who were non-responders because ACR-pedi was less than 10%. Second group contained 4 patients, who had ACR-pedi more than 10%. The megerment of genotypes of genes of folate cycle, such as 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), 5,10methylenetetrahydrofolate reductase C677T and A1298C variants (MTHFR-677 and MTHFR129) by polymerase chain reaction (PCR) was performed for all patients.

Results

In II group effectiveness of therapy according ACR-pedi was from 30% to 70% in 75% of children and more then 70% - in 25% of patients. In general, MTR gene indicated AA-genotype in 50% of patients, AG and GG-genotypes - in 25%; MTRR gene was performed with AA-genotype in 25%, AC-genotype in 12.5% and CC-genotype in 62.5%. MTHFR1298 gene was presented in 50% of patients with AA-alleles, in 25% - with AC and CC-genotypes. 50% of children had CC-genotype of MTHFR677 gene and other 50% - AC-genotype of MTHFR677 gene. CC-genotype of MTHFR1298 gene more frequently was determined in II group (p< 0.01). In group of non-responders AA-genotype of MTR gene was found more frequent in comparison with patients from group II (p< 0.01).

Conclusion

Response to standard therapy in patients with JIA depends on time of prescription of MTX and genotype of MTHFR1298 and MTR genes.

Disclosure(s)

Nothing to disclose
P79 Pharmacokinetics of sufentanil in critically ill neonates
Authors: Pokorná P , Šíma M , Koch B , Tibboel D , Slanař O
Published: May 2019

Background

Sufentanil is a potent synthetic opioid increasingly used as an analgesic drug for pain treatment in critically ill neonates. Clinical studies concerning the pharmacokinetics (PK) of sufentanil administered as a bolus or continuous infusion in neonates are sparse and a population model has been developed for critically ill children beyond the newborn period. The aim of our study was to determine the PK of sufentanil in critically ill neonates treated with continuous sufentanil infusion for pain management (prophylactic and therapeutic use).

Methods

Eight term neonates (birth weight 2.60–4.30 kg; postnatal age 2–96 h) were treated with sufentanil (initial bolus 0.1–0.5 µg/kg i.v. administered for 5 minutes followed by continuous infusion 0.1–0.5 µg/kg per hour i.v.). Sufentanil plasma concentrations were determined using a UPLC-MS/MS assay. Totally 159 sufentanil concentrations were measured (8–27 measurements per patient). Individual sufentanil PK parameters were calculated in a two-compartmental PK model with first-order elimination kinetics based on individual demographic and clinical data and observed sufentanil plasma levels using MWPharm++ software (MediWare, Prague, Czech Republic). The sufentanil population PK model was individualized to maximize fitting of the simulated PK profile curve with observed concentration points. The fitting was performed using Bayesian method.

Results

Median (IQR) sufentanil central and total volume of distribution, clearance, and distribution and elimination half-life were 4.7 (4.2–5.2) L/kg and 11.8 (9.9–14.2) L/kg, 0.552 (0.415- 0.671) L/h/kg, and 0.0264 (0.0260–0.0264) h and 15.7 (13.4–19.2) h, respectively.

Conclusion

We observed similar sufentanil PK parameters (preliminary results) as described previously in literature. However, further studies with more patients are needed.

Funding

This study is supported by a Charles University project Progres Q25, SVV 260373 and a project MH CZ-DRO - VFN64165, and by an unrestricted research grant of the Intensive Care of the ErasmusMC-Sophia Children’s Hospital.

Disclosure(s)

Nothing to disclose
P80 Objective pharmacodynamic evaluation of doxapram in preterm infants
Authors: Poppe JA , van Weteringen W , Völler S , Goos TG , Reiss IKM , Simons SHP
Published: May 2019

Background

Pharmacodynamic evaluation is challenging in neonatal clinical care, and often based on subjective human interpretation of clinical signs and the available ‘snapshot’ of physiological parameters. High frequency data (≥ 1Hz) of bedside patient monitors provide the opportunity of continuous and objective drug evaluation.1 This study investigates the predictive value of continuously available vital and ventilatory parameters to evaluate doxapram therapy. Doxapram is a respiratory stimulant to avoid mechanical ventilation and adverse outcomes of hypoxemia in preterm infants.2

Methods

Preterm infants admitted to a level III NICU centre who received doxapram therapy were eligible for inclusion. Stored vital and ventilatory parameters were retrospectively analysed. Multivariate analysis was performed to identify variables that influenced therapy failure (intubation or death) or success. Variables with a p value < 0.1 in univariate analysis were included in the multivariate analysis. Additionally, the ΔSpO2/FiO2-ratio was calculated by subtracting the median SpO2/FiO2-ratio 1 day after therapy from the median SpO2/FiO2-ratio 1 day before therapy.

Results

The first episode of doxapram treatment was analysed in a total of 61 preterm infants with a median postnatal age at therapy start (PNA) of 3.0 weeks (IQR; 2.0–3.6). The success rate of doxapram therapy was 57%. Out of all parameters, the SpO2/FiO2-ratio showed to be the most indicative for therapy outcome. The predictive model included the ΔSpO2/FiO2-ratio, the PNA, the administration of a loading dose at start, and intubation within 24 hours before the start of doxapram (area under the curve of 0.828). The ΔSpO2/FiO2-ratio was inversely associated with therapy outcome (OR 0.26, CI 95% 0.07–0.83; p = 0.03).

Conclusion

The ΔSpO2/FiO2-ratio between 1 day before and 1 day after start of the therapy is predictive of failure or success of doxapram therapy. The use of physiological data shows potential in the pharmacodynamic evaluation of doxapram therapy.

References

Flint R, Weteringen WV, Voller S, Poppe JA, Koch BC, Groot R, et al. Big data analyses for continuous evaluation of pharmacotherapy: A proof of principle with doxapram in preterm infants. Curr Pharm Des. 2017.

Poets CF, Roberts RS, Schmidt B, Whyte RK, Asztalos EV, Bader D, et al. Association Between Intermittent Hypoxemia or Bradycardia and Late Death or Disability in Extremely Preterm Infants. JAMA. 2015;314(6):595–603.

Disclosure(s)

Nothing to disclose
P105 Ambulatory study center at the University of Basel Children’s Hospital (UKBB)
Authors: Werner C , Santoro R , Bielicki J
Published: May 2019

Background

Many drugs authorized in Europe and the United States are inadequately studied in children. SwissPedNet Funding has boosted the development of specialized and professional pediatric centers for clinical studies in Switzerland tasked with executing compliant, reliable and family-centered clinical research. The University of Basel Children`s Hospital (UKBB) is one of the pediatric clinical study centers.

Methods

The Department for Clinical Research in Basel consists of the study center for adults at University Hospital Basel (USB) and the Ambulatory Study Center (ASZ) focusing on pediatric studies at the UKBB. The latter was established in 2015, and consists of a specialized team, including a medical director, medical coordinator, medical specialists in pediatrics as well as a team of study nurses.

The ASZ supports and promotes clinical studies with and for infants and children for external and internal sponsors in various therapeutic areas such as oncology, cardiology, pneumology, nephrology, neuropediatrics, orthopaedics and infectious diseases. The full range of activities for executing the approved clinical study protocol can be offered, including planning, implementation, budgeting, coordinating, monitoring and archiving as well as collaboration with all required hospital departments.

Results

Up to now, the ASZ has enrolled around 600 children in clinical trials, with 6 studies completed and 12 studies ongoing. A comprehensive Quality Management system was established and SOPs were jointly created with the adult study center. A digital clinical study request form is available for sponsors via the website.

Conclusion

We see an increased demand for pediatric clinical studies across all age ranges and therapeutic areas. We envision a center of excellence with a pool of fully trained study nurses to accommodate and centrally organize all pediatric studies in the UKBB. Parent engagement and patient inclusion is one critical step to further improving healthcare for pediatric patients through highest quality clinical research.

Disclosure(s)

Nothing to disclose
P106 Impact of a computerised physician order entry system on medication safety in paediatrics
Authors: Wimmer S , Toni I , Trollmann R , Rascher W , Neubert A
Published: May 2019

Background

One of the most critical steps in the medication process on paediatric wards is the drug prescription.1 Studies have shown that the use of electronic systems may improve the quality of prescribing and reduces medication errors in paediatric inpatients.2

This study aims to investigate the impact of a computerised physician order entry (CPOE) system (incl. decision support for dosing) on adverse drug reactions (ADR) and medication errors (ME) in comparison to paper-based prescribing and documentation.

Methods

A prospective pre-post study was conducted at a general paediatric ward. All patients aged 17 years or younger that were treated for at least 24 hours during the study periods (5 months pre and post implementation) were observed. Adverse events were identified by intensive chart review.

The primary outcome measure was the incidence of clinically relevant ADRs and MEs. Events were assessed regarding causality (WHO), severity (WHO and additionally Dean & Barber for MEs) and preventability (Shumock).3

Results

338 patients with medication were included in the paper-based prescribing cohort (phase I) and 320 patients with medication in the electronic prescribing cohort (phase II). Median age was 7 (IQR 2 - 14) and 6 (IQR 1 - 13), respectively. In each cohort patients received a median number of 4 different drugs.

Potentially harmful MEs were less often observed in the cohort with electronic prescribing (n=231 vs. n=549). The mean number per patient significantly decreased from 1.62 to 0.72 (p< 0.05).

During the hospitalisation 2.1% (n=7) patients in phase I and 2.8% (n=9) in phase II experienced clinically relevant ADRs whereof two (0.6%) in each cohort originated from MEs.

Conclusion

The implementation of a CPOE system significantly reduces medication errors, particularly those potentially harming patients but has less impact on ADRs.

References

Fortescue EB, Kaushal R, Landrigan CP, McKenna KJ, Clapp MD, Federico F, et al. Prioritizing strategies for preventing medication errors and adverse drug events in pediatric inpatients. Pediatrics. 2003;111(4Pt 1):722–9.

Maaskant JM, Vermeulen H, Apampa B, Fernando B, Ghaleb MA, Neubert A, et al. Interventions for reducing medication errors in children in hospital. The Cochrane database of systematic reviews. 2015;3:Cd006208.

Dean BS and Barber ND. A validated, reliable method of scoring the severity of medication errors. Am J Health Syst Pharm 1999;56(1):57–62.

Disclosure(s)

Nothing to disclose
O18 Therapeutic delivery during breastfeeding: a feasibility study
Authors: Maier T , Peirce P , Baird L , Whitehouse SL , Slater NKH , Beardsall K
Published: May 2019

Background

At an age when breastfeeding is the optimal nutritional support for infants, enteral drug delivery can be physically and emotionally challenging for parents. Delivery during breastfeeding could serve as an alternative to currently existing approaches. This study aimed to explore its feasibility and acceptability.

Methods

Vitamin B12 was administered as part of a single-centre feasibility study to breastfed infants at the University of Cambridge Addenbrooke´s Hospital NHS Trust. Hereby a solid formulation (tablet) was placed inside an ultra-thin silicone nipple shield, and worn by a mother during the feed. The study investigated i.) quantitative changes in B12 blood serum levels at baseline and 6–8 hours after the study feed, ii.) mothers’ expectations and experiences via a mixed method approach by a single investigator. Local ethics approval was obtained prior to any study procedures being undertaken (18/LO/0551).

Results

Twenty dyads completed the study protocol. In all cases, no residual tablet was left after the feed, and the tablet’s presence within the shield did not appear to impact feeding. A pharmacokinetic-dependent vitamin B12 increase to 1871 pg/mL (610–4981 pg/mL) from a baseline of 533 pg/mL (236–925 pg/mL) was observed. Mothers described the nipple shield´s surprising ease of use and comfort for delivery, not affecting normal breastfeeding behaviour/sensation, while decreasing infant/maternal distress compared to the use of an oral syringe. All mothers expressed their wish for this approach to become available to parents in the future. Reasoning included the desire (1) of parents to have choices in relation to their infants’ health, (2) to replace a medical intervention with one that was felt to be more ‘natural’.

Conclusions

This study showed that solid formulations can be used for therapeutic delivery whilst breastfeeding and is viewed by mothers as advantageous compared to currently available methods.

Disclosure(s)

Funding

The research was supported by a WD Armstrong PhD studentship for the Application of Engineering in Medicine, University of Cambridge, the German Academic Scholarship Foundation, and the Kurt Hahn Trust, University of Cambridge. Competing interests (applicable to all authors): None declared.
O37 Use of albendazole in children with asymptomatic toxocariasis
Authors: Garcia Bournissen F , Moroni S , Gonzalez N , Moscatelli G , Ballering G , Altcheh J
Published: May 2019

Background

Human toxocariasis is highly prevalent and its global importance may be greatly underestimated. Toxocariasis occurs mainly in childhood by ingestion of parasite eggs from contaminated environment. During migration in human tissues the Toxocara larvae can cause several symptoms including eye involvement, but the majority of patients are asymptomatic. Eosinophilia is a marker of activity of this disease. There are no studies supporting the treatment of asymptomatic patients.

Methods

To evaluate the effectiveness of albendazole (10–15 mg/kg/day BID for 15 days) a randomized, placebo-controlled trial was carried out in asymptomatic children (ClinicalTrials.gov #NCT00755560). Treatment response was defined as mean absolute reduction in eosinophil counts, 12 months after treatment.

Demographic, complete blood count, liver and renal function and stool parasite exam were assessed at diagnosis, and every 4 months during follow up. Inclusion criteria: age 2 to 15 years, reactive toxocara excretory-secretory substances (TES) by ELISA, eosinophils >1100/mm3, normal fundoscopy and non geohelmintic infection.

Results

The 45 enrolled subjects, median age 5.3 years (range 2–13), were randomized in a 1: 1 relationship.

At 12-month follow-up, eosinophil median was: 1008/mm3 (IQ 25-75680 to 2023) in placebo group and median of 1360/mm3 (IQ 25-75761 to 2226) in albendazole group (p = 0.37).

Kinetics of specific antibody titers by the ELISA showed an erratic pattern. No differences were observed in the values between the 2 treatment groups.

Both groups had minor adverse events and no patient needed to discontinue medication. In asymptomatic patients with toxocariasis, albendazole was not effective to reduce eosinophil counts.

Conclusion

Given that toxocariasis is a neglected disease, in order to evaluate the effectiveness of albendazole or other drugs, further studies need to be conducted.

Disclosure(s)

Nothing to disclose
P10 Reporting of offspring data in diabetes, HIV infection and hypertension trials during pregnancy: a systematic review
Authors: Aurich B , Martin-Montoya T , Zhang D , Jacqz-Aigrain E
Published: May 2019

Background

According to international guidelines clinical trials are conducted during pregnancy to evaluate benefits and risks of medicines for both the mother and her offspring. Consolidated Standards of Reporting Trials (CONSORT) reporting criteria apply to these trials and should include safety data on the offspring. The safety of maternal treatments is a key issue for health care professionals and parents. Diabetes, human immunodeficiency virus (HIV) infection and hypertension are among the most frequent chronic diseases worldwide in women of child bearing potential. The objective of this systematic review was to analyse offspring data reported in clinical trials conducted in pregnant women receiving chronic drug treatment for one of these conditions.

Methods

Pubmed and Embase (01/01/1997–31/12/2017) were searched for drug trials in pregnant women with diabetes, HIV infection or hypertension. Titles and abstracts were screened, followed by a full text review of eligible articles. Inclusion criteria were interventional clinical trials in pregnant women treated with chronic medication and full text in English. Trial characteristics, maternal and offspring data were extracted. Data was summarised by disease and study. Twelve key items were considered for the offspring. The protocol was registered on PROSPERO (CRD42017057024).

Results

Overall, 196 articles reporting 132 clinical trials (diabetes n=55; HIV n=59; hypertension n=18) were included. The number of births were frequently not reported (diabetes 40%; HIV 24%; hypertension 56%). Congenital malformations were infrequently reported with sufficient detail (diabetes 27%; HIV 34%; hypertension 6%). Similar observations were made for other key items (e.g. foetal losses, neonatal deaths, birth weight corrected for gestational age).

Conclusions

Underreporting of key data for the offspring was frequent in publications of clinical trials in pregnant women with diabetes, HIV infection or hypertension making the assessment of the benefit-risk ratio of treatment options during pregnancy difficult.

Disclosure(s)

Nothing to disclose
O05 Physiologically based pharmacokinetic modelling to characterize acetaminophen pharmacokinetics and NAPQI formation in non-pregnant and pregnant women
Authors: Mian P , van den Anker JN , van Calsteren K , Annaert P , Tibboel D , Pfister M , Allegaert K , Dallmann A
Published: May 2019

Background

Little is known about the pharmacokinetics (PK) of acetaminophen during different stages of pregnancy. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict acetaminophen PK throughout pregnancy.

Methods

PBPK models for acetaminophen and its metabolites were developed in non-pregnant and pregnant women. Physiological and enzymatic changes in pregnant women expected to impact acetaminophen PK were considered. The models were evaluated using goodness-of-fit-plots and through comparison of predicted PK profiles with in-vivo PK data. Predictions were performed to illustrate the concentrations at steady state (Css-mean), used as indicator for efficacy of acetaminophen achieved following 1000 mg q6h. Furthermore, as measurement for potential hepatotoxicity, the molar dose fraction of acetaminophen converted to NAPQI was estimated.

Results

PBPK models successfully predicted the PK of acetaminophen and its metabolites in populations of non-pregnant and pregnant women. Predictions resulted in lowest Css-mean in the third trimester (4.5 mg/L), while Css-mean was 6.7, 5.6 and 4.9 mg/L in non-pregnant, first and second trimester populations, respectively. Assuming a constant increased activity of CYP2E1 throughout pregnancy, the molar dose fraction of acetaminophen converted to NAPQI was highest during the first (11.0%), followed by second (9.0%) and third trimester (8.2%), compared to non-pregnant women (7.1%).

Conclusion

Risk for drug related hepatotoxicity in pregnant women might be increased as more NAPQI is produced during pregnancy compared to non-pregnant women, especially during the first trimester. However, lack of information on the detoxifying capacity precludes any strong conclusions.

Disclosure(s)

Paola Mian received a Short term Minor (STM-2017) grant from the Stichting Sophia Kinderziekenhuis fonds to conduct this research.
P13 Serious adverse reactions and off label and unlicensed drug use in children – decade of pharmacovigilance study in Serbia
Authors: Bajcetic M , Joksimovic J
Published: May 2019

Background

Off label (OL) and unlicensed (UL) drug use in children is a widespread global problem. Previous study showed that only 66% of all available drugs for children is with licence in Serbia.1 Data on safety of medicines in children remain lacking, so the key intervention for the effective use of medicine is safety monitoring. Therefore, the aim of this study is to evaluate safety implication of OL and UL drug use in children up to 12 years old.

Method

We conducted a retrospective study based on reports of suspected adverse reactions (ADRs) collected from 2008. to 2018. by Medicines and Medical Devices Agency of Serbia, using the Medical Dictionary for Regulatory Activities and organized by System Organ Class. Sources of information about medicines including vaccines (license, drug formulation, etc.) are the Summary of Product Characteristics and Serbia´s official drug registry.

Results

Within 10 years, we observed 1595 ADRs. Vaccines, antineoplastic and antimicrobial drugs were the most frequently pharmacotherapeutic subgroups involved. Out of total number of observed ADRs, 433 (28%) were serious; 189 of them led to hospitalization, 31 to life threatening conditions and 7 were fatal. More than a half (63%) of serious ADRs were detected in children for the age group of 28 days - 23 months, followed by the age group of 2 to 11 years (34%) and finally by age group of 0 to 27 days (3%). Serious ADRs were detected in boys (55%) as well as in girls (45%). Out of total number of registered only 3% (46) of ADRs were associated with off-label use; 18 of them were serious, 7 led to life threatening conditions and 3 were fatal.

Conclusion

This research provided new insight on the factors such as OL and UL use, that might increase the risk of serious ADRs in children.

References

Bo&zbreve;ić B, Stupar S, Stupar D, Babić U, Bajčetić M. Availability of pediatric-evaluated formulations in Serbia. Indian J Pharmacol 2017 Mar-Apr;49(2):189–193

Disclosure(s)

Nothing to disclose
P15 Lacosamide monitoring in the serum of children with refractory epilepsy
Authors: Kronenfeld N , Kohn E , Lezinger M , Brandriss N , Heyman E , Bar-Chaim A , Berkovitch M
Published: May 2019

Background

Lacosamide is indicated for various types of refractory epilepsy and as adjunctive therapy to other antiepileptic medications. Data on monitoring serum levels of lacosamide in pediatric patients is scarce.

Objective

To evaluate the correlation between serum levels of lacosamide and the tolerability in children with refractory epilepsy.

Methods

The medical records of 22 children with refractory epilepsy treated with lacosamide at Assaf Harofeh Medical Center were reviewed. Trough serum levels of lacosamide was measured using HPLC and correlated with its efficacy and safety.

Results

Mean age of the children was 11 ± 4 (3–18) years. Median lacosamide daily dose was 9.3 (6.6–11) mg/kg and median plasma concentration was 7.1 (5.9–11.9) ug/ml. The therapeutic range of lacosamide serum concentration is 10 to 20 ug/ml. No change in seizures frequency was reported in 21.4% of children with lacosamide concentrations below 10 ug/ml. However, in 40% of the children, reduction of the seizures frequency was reported when serum concentration was above 10 ug/ml. No serious adverse events were reported during therapy. The prospective part of the study was initiated, and the first patients were recruited.

Conclusion

Large studies, preferably prospective, on lacosamide serum monitoring including information on correlation with efficacy and safety are warranted.

Disclosure(s)

Nothing to disclose
P25 Comparison of renal function estimation methods in critically ill children: a pilot study
Authors: Dhont E , Van Der Heggen T , De Jaeger A , Willems J , De Baere S , Croubels S , Vande Walle J , De Paepe P , De Cock P
Published: May 2019

Background

Accurate assessment of renal function is crucial in intensive care to guide therapy. Both acute kidney injury and augmented renal clearance (ARC) may compromise outcome. Common formulas to estimate glomerular filtration rate (GFR) are unreliable in critically ill adults.1 A comparison of a gold standard technique to assess GFR with these formula-based estimations has never been reported in pediatric intensive care (PICU) patients. Our aim was to evaluate the feasibility of measuring plasma iohexol clearance (CLIOHEX) for GFR assessment in critically ill children and to compare CLIOHEX with estimated GFR using the modified Schwartz formula (eGFRSchwartz).

Methods

A prospective, interventional study was conducted at the PICU of the Ghent University Hospital, Belgium. Critically ill children without chronic kidney disease were included. After injection of a weight-dependent bolus of iohexol, serial blood samples (n=6) were taken over a 6-hours interval. CLIOHEX was compared to eGFRSchwartz. Correlation between both methods was assessed by a Pearson´s correlation coefficient (r).Bland-Altman plots were evaluated to assess bias and limits of agreement (LOA). ARC was defined as a GFR exceeding normal values for age plus two standard deviations.

Results

40 patients, median age 16 months (range 15 days -13,6 years), 72,5% males, were included. No adverse effects related to iohexol were observed. Median CLIOHEX was 121 ml/min/1.73m2 (range: 43–221 ml/min/1.73m2). ARC was present in 20 patients based on CLIOHEX. Median eGFRSchwartz was 81 ml/min/1.73m2 (range: 31–131 ml/min/1.73m2). Only 1 patient was identified with ARC by eGFRSchwartz. eGFRSchwartz was systematically lower than CLIOHEX. There was a good correlation between CLIOHEX and eGFRSchwartz (r = 0,69; p< 0,01). Bias was 34 ml/min/1.73m2 with LOA (-24,5; 93 ml/min/1.73m2)

Conclusion

CLIOHEX was safely used to measure true GFR in critically ill children. eGFRSchwartz systematically underestimates GFR, especially in patients with ARC and seems not reliable in this patient population.

Reference

Baptista JP, Neves M, Rodrigues L, Teixeira L, Pinho J, Pimentel J ( 2014) Accuracy of the estimation of glomerular filtration rate within a population of critically ill patients. J Nephrol. 27:403–410.

Disclosure(s)

Nothing to disclose
P37 Reference ranges of blood NT-proBNP in paediatric heart failure and healthy controls: compilation of literature data
Authors: Gangnus T , Suessenbach FK , Makowski N , Burdman I , Laeer S , Burckhardt BB
Published: May 2019

Background

N-terminal pro-brain natriuretic peptide (NT-proBNP) is a valuable biomarker for diagnosis and prognosis of heart failure in adults, included into the European Society Guidelines for heart failure (2016).1 It is also considered as a diagnostic and follow-up marker in paediatric heart failure. The aetiology of paediatric heart failure is heterogeneous and maturation of the cardiac and neurohumoral system influences NT-proBNP levels. Since substantial information is mandatory to enable a long-term follow-up of children with heart failure, the aim was to collect published paediatric NT-proBNP data.

Methods

In January 2019, a literature search using PubMed was performed comprising the following keywords: NT-proBNP, heart failure/dilated cardiomyopathy/congenital heart defect/congenital heart disease/healthy and child/neonate/toddler/infant/paediatric. Eligible publications had to determine levels of NT-proBNP in plasma or serum in paediatric heart failure or healthy children (0–18 years) with the Roche NT-proBNP-immunoassay.

Results

The search resulted in 343 records, of which 95 measured NT-proBNP in paediatric controls or heart failure. Of them, 48 studies were excluded due to the use of other immunoassays. Following, 47 studies were included into the analysis of which 27 reported NT-proBNP levels in 3435 healthy children and 38 NT-proBNP concentrations in 1885 children with heart failure. The age range of reported levels comprised the day of birth up to 18 years in both groups. The data set revealed that younger children have higher NT-proBNP values than older children and that heart failure patients had increased NT-proBNP levels compared to healthy controls which are also dependent on the severity of disease.

Conclusion

The literature search and analysis confirmed that NT-proBNP is an important marker for the detection of heart failure and classification of disease severity in children. Thus, the compiled data set forms a solid data basis for long-term follow-up of a paediatric patient population with heart failure.

References

Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The task force for the diagnosis and treatment of acute and chronic heart failure of the european society of cardiology (ESC)developed with the special contribution of the heart failure association (HFA) of the esc. Eur Heart J 2016;37(27):2129–200.

Disclosure(s)

Tanja Gangnus, Fabian K. Suessenbach, Nina Makowski, Ilja Burdman, Stephanie Laeer, Björn 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 (FP/2007–2013) under grant agreement n°602295 (LENA).
P39 Establishment of the swiss database for dosing medicinal products in pediatrics
Authors: Giger E , Glauser A , Panis D , Tilen R , Berger C
Published: May 2019

Background

Drug therapy in children is challenging. Due to the lack of licensed drugs for paediatric use, off-label or unlicensed prescription is frequent. To improve quality and safety of prescription of medicinal products for children in Switzerland, the requirement to create and continuously run a national database was added in the revision of the therapeutic products act (TPA Art. 67a). The task of operating the database was given to SwissPedDose, an association representing eight Swiss children’s hospitals, the Swiss Society of Paediatrics (SGP) and the Swiss Association of Public Health Administration and Hospital Pharmacists (GSASA).

Methods

Substances used in three therapeutic areas ‘general paediatrics’, ‘infectious diseases’ and ‘neonatology’ are selected according to their frequency of use in the eight participating hospitals. Dosage data of substance-indication pairs are requested from the hospital pharmacists. Based on these data and literature review a dosage suggestion consisting of substance, indication, route of administration, dose, daily repetitions and, if applicable, additional remarks is then elaborated by a specialised pharmacist of SwissPedDose. This suggestion is then discussed by experienced physicians delegated from the eight clinics. The elaboration, discussion and agreement on a national dosage recommendation takes place and is documented in an online platform specially programmed for this structured harmonisation process. Once an agreement has been achieved, the national dosage recommendation is sent to the eight participating clinics and published in a free accessible public database.

Results

As of December 31st 2018, 195 dosage recommendations for children including 87 indications and 54 substances have been harmonised and published and are available for medical professionals on https://swisspeddose.ch/database.

Conclusion

The goal of published recommendations for 100 substances by March 2021 is feasible to reach due to interprofessional collaboration. SwissPedDose may thus contribute to a more efficient and safe use of drugs prescribed to children in Switzerland.

Disclosure(s)

Source of Funding: Project funded by the Federal Office of Public Health. Conflict of interest: None, for all listed authors.
P51 A combined experimental approach to assess intestinal drug absorption in early childhood
Authors: Kiss M , Nicolaï J , Heuvel JJMW van den , Mbasu R , Botden SM , Koenderink JB , Russel FGM , Ungell A-L , de Wildt SN
Published: May 2019

Background

Drug transporters and metabolizing enzymes located in the epithelial lining of the intestine limit or enhance systemic drug exposure. During child development, the abundance and activity of these transporters and enzymes - determining how fast and how much of a drug is being absorbed into the circulation - changes from birth to adolescence. As most drugs given to children are taken by mouth, the aim of this project is to study the abundance and activity of transporters and metabolizing enzymes, involved in the intestinal absorption of drugs.

Methods

The ex vivo Ussing chamber with pediatric small intestinal tissue is applied to evaluate intestinal drug absorption and metabolism.1 Transport and metabolism of a selection of drug molecules is assessed across these tissues by sampling the donor and receiver compartment at different intervals and sample analysis by LC-MS/MS. Viability, functionality and integrity of the tissues are monitored using electrophysiological parameters (dP, R, I). Ussing chamber experiments are combined with a targeted proteomics approach to quantify drug transporter and metabolizing enzyme abundance in these tissues.

Results

An Using chamber method has been successfully set up using both adult and pediatric intestinal tissue. To date samples from three children of different ages have been evaluated and show promising results. Tissue from the same patients has been stored for proteomics analysis.

Conclusion

The Ussing method presents an innovative, feasible approach to study active intestinal transport in children. Further studies are now underway to elucidate age-related variation in intestinal transport and metabolism.

Reference

Sjöberg Å, Lutz M, Tannergren C, Wingolf C, Borde A, Ungell AL:Comprehensive study on regional human intestinal permeability and prediction of fraction absorbed of drugs using the Ussing chamber technique. Eur J Pharm Sci 2013 Jan 23;48(1–2):166–80.

Disclosure(s)

The collaboration project is financed by the Ministry of Economic Affairs by means of the PPP Allowance made available by the Top Sector Life Sciences & Health to stimulate public-private partnerships. Johan Nicolaï, Richard Mbasu and Anna-Lena Ungell are employees of UCB Biopharma SPRL.
P54 KIDS-STEP: a swiss multi-centre RCT on effectiveness of adjunct betamethasone therapy in hospitalised children with community acquired pneumonia
Authors: Kohns Vasconcelos M , Santoro R , Coslovsky M , van den Anker J , Bielicki JA
Published: May 2019

Background

The incidence of community-acquired pneumonia (CAP) in young children is high (20- 30/1000 child-years) and is associated with a high rate of hospitalisation (around 10/1000 child-years). In adults, a benefit of adjunct corticosteroids on time to clinical stability and hospital discharge has been observed and confirmed in systematic reviews and meta-analyses. In contrast, only few small trials have addressed the potential impact of oral steroid treatment in CAP during childhood. The purpose of this study is to concurrently evaluate whether adjunct treatment with corticosteroids in children hospitalised with CAP is more effective in terms of the proportion of children reaching clinical stability and whether such adjunct treatment is no worse in terms of CAP relapse.

Methods

Children in KIDS-STEP1 receive either oral betamethasone or oral placebo dosed once daily for two consecutive days. We include 700 children from age 1 weighing at least 7 kilograms and up to a body weight of 35 kilograms and age below 10 years hospitalised for CAP using a clinical diagnosis.

Co-primary outcomes are

(a) The proportion of children clinically stable at 48 hours after randomisation. (b) The proportion of children with CAP-related readmission within 28 days after randomization. Secondary outcomes will be captured to further evaluate the efficacy and safety of adjunct oral steroids in the management of childhood CAP, including proportion of children experiencing solicited side effects of the trial treatment and/or serious adverse events, time to hospital discharge after index hospitalisation in days, time away from routine child care and away from work (for parents) in days up to 28 days after randomisation and total antibiotic exposure in days up to 28 days after randomisation.

Results

Enrolment started in November 2018 and is currently proceeding at approximately 1 participant per participating hospital per week.

References

Study registration: BASEC - EKNZ 2018–00563

Disclosure(s)

Nothing to disclose
Recreational and ergogenic substance use and substance use disorders in elite athletes: a narrative review
Authors: McDuff David , Stull Todd , Castaldelli-Maia João Mauricio , Hitchcock Mary E , Hainline Brian , Reardon Claudia L
Published: May 2019

Background

Substances from various classes may be used for recreational purposes, self-treatment or to boost performance. When substance use shifts from occasional to regular, heavy or hazardous use, positive and negative effects can develop that vary by substance class and athlete. Regular use of recreational or performance enhancing substances can lead to misuse, sanctions or use disorders.

Objective

To review the prevalence, patterns of use, risk factors, performance effects and types of intervention for all classes of recreational and performance enhancing substances in elite athletes by sport, ethnicity, country and gender.

Methods

A comprehensive search was conducted to identify studies that compared the prevalence and patterns of substance use, misuse and use disorders in elite athletes with those of non-athletes and provided detailed demographic and sport variations in reasons for use, risk factors and performance effects for each main substance class.

Results

Alcohol, cannabis, tobacco (nicotine) and prescribed opioids and stimulants are the most commonly used substances in elite athletes, but generally used at lower rates than in non-athletes. In contrast, use/misuse rates for binge alcohol, oral tobacco, non-prescription opioids and anabolic-androgenic steroids are higher among athletes than non-athletes, especially in power and collision sports. Cannabis/cannabinoids seem to have replaced nicotine as the second most commonly used substance.

Conclusions

Substance use in elite athletes varies by country, ethnicity, gender, sport and competitive level. There are no studies on substance use disorder prevalence in elite male and female athletes and few studies with direct comparison groups.