bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOSE-FINDING STUDY AND PHARMACODYNAMIC ASSESSMENT OF PROPOFOL FOR (SEMI-)ELECTIVE INTUBATION IN NEONATES
Authors: Smits Anne , Thewissen Liesbeth , Caicedo Alexander , Nicolaï Johan , Annaert Pieter , Naulaers Gunnar , Allegaert Karel 
Published: December 2015

IntroductionThe optimal propofol dose and its safety for procedural sedation in neonates is controversial. The aim of this study was to perform a prospective propofol dose-finding study with pharmacodynamic (PD) assessment during (semi-)elective intubation in neonates.MethodsPatients were stratified in 4 groups by postmenstrual and postnatal age. The first patient in each group received 1 mg/kg intravenous propofol bolus. Dosing for the next patient was determined using the up-and-down method. Propofol ED50 doses [effective dose for successful intubation (as well as extubation in INSURE -intubation, surfactant, extubation-cases) in 50% of patients] were calculated, with simultaneous assessment of clinical scores, continuous vital sign monitoring and propofol blood concentrations (3 and 12h after dosing).ResultsThirty-five neonates (weight 540–3290 g) were included. Using initial and total propofol dose ranges of 0.5–2 and 0.5–4.5 mg/kg respectively, median propofol ED50 range for preterm neonates <10 days was 0.480–1.287 mg/kg. Clinical recovery was not attained at the end of the scoring period (21 minutes). A median decrease in mean arterial blood pressure (MABP) between −29.41% and −39.09% from baseline, and a short-lasting decrease in peripheral (SaO2) and regional cerebral (rScO2) oxygen saturation was documented. Variability in MABP, SaO2 and rScO2 was not explained by weight, age or propofol concentrations.ConclusionsLow propofol doses sufficiently sedate neonates for intubation, but clinical recovery takes time and is accompanied by permissive hypotension. Propofol ED50 doses are provided and need integration in a prospective validation approach. Finally, feasibility of continuous monitoring for neonatal pharmacodynamic research was demonstrated.
PEDIATRIC DRUG TRIALS IN CHINA
Authors: Hao Guo-Xiang , Wang Xiao-Ling , Shen A-Dong , Jacqz-Aigrain Evelyne , Zhao Wei 
Published: December 2015

Background and objectiveThe introduction of the Pediatric Regulation by the European Union, together with the renewal of the Pediatric Rule by the US Food and Drug Administration on the requirements for pediatric labeling made it mandatory for sponsors to develop drugs for the pediatric population and promotes the pediatric drug trials in Europe and US. However, very little is known about the situation of pediatric drug trials in other countries, particularly in China, home to nearly 300 millions children. In order to support the global research in pediatric drug development and clarify the specific characteristics of pediatric drugs trials in China, we analyzed the drug trials registered in the Chinese Clincial Trial Registry database.MethodsThe pediatric drug trials registered in Chinese Clincial Trial Registry database between 2007 and 2014 were analyzed. The following information was extracted from the database by two authors: type of the trial, registered time, drug name, inclusion and exclusion criteria, population, number of patients, and sponsor.ResultsAmong all (4786) trials registered, 729 trials (15.2%) involved the pediatric population, and only 308 trials (6.4%) were pediatric drug trials. From 2007 to 2013 pediatric drug trials increased from 3 to 121. There were 66 pediatric drug trials including Chinese traditional medicine.ConclusionOur results demonstrated for the first time the situation of pediatric drug trials in China. Consistent with the initiatives of promoting pediatric drug development in Europe and US, the pediatric drug trial in China made a significant progress after 2012. The pediatric drug legislation is urgently needed in China.
POPULATION PHARMACOKINETICS OF INTRAVENOUS ALBUTEROL IN CHILDREN WITH STATUS ASTHMATICUS
Authors: Vet Nienke J , de Winter Brenda CM , de Wildt Saskia N , der Nagel Bart CH van , AJ Knibbe Catherijne , Koninckx Muriel , de Hoog Matthijs , Koch Birgit CP 
Published: December 2015

ObjectivesTo develop a population pharmacokinetic model of R-albuterol and S-albuterol for children suffering from status asthmaticus following continuous intravenous administration.MethodsAt the pediatric ICU 19 children suffering from severe status asthmaticus were treated using continuous intravenous albuterol in doses based on clinical symptoms (range 0.1–10 µg/kg/min). During therapy 111 blood samples were collected and analysed for R- and S-albuterol using a validated LC/MS-MS method. A population pharmacokinetic analysis was conducted using non-linear mixed effects modelling (NONMEM 7.2). Data was logarithmically transformed. Model selection criteria were decrease in objective function, diagnostic plots and NPDE. The covariates (range) analysed were bodyweight (7.8–70 kg), age (0.8–15.3 years), creatinine concentration (17–70 µmol/L), alanine transaminase (5–29 IU/L), and urea (1.6–4.8 mmol/L).ResultsA two-compartment model with separated clearance for R- (16.3 L/h) and S-albuterol (8.8 L/h) best described the data. Separated values for central volume of distribution (12.9 L), peripheral volume of distribution (45.2 L) and intercompartmental clearance (20.0 L/h) did not improve the model. Between-subject variability was described for clearance of R-albuterol (42%), clearance of S-albuterol (37%) and central volume of distribution (280%). Weight is a significant covariate using a power function. The exponent of the powerfunction was fixed at 0.75 for clearance and intercompartmental and at 1 for central and peripheral volume of distribution. Estimation of the exponent resulted in similar values and did not improve the model. No other covariates were identified.ConclusionThe population pharmacokinetics of R- and S-albuterol are described. This model can be used to evaluate the correlation between albuterol pharmacokinetics and effect in a population pharmacokinetic-pharmacodynamic analysis.
MAPPING IN VITRO AND IN VIVO DERIVED CYP2C9 AND CYP2C19 ONTOGENY FUNCTIONS: A CRITICAL COMPARISON BETWEEN VARIOUS ONTOGENY MODELS
Authors: Salem Farzaneh , Johnson Trevor , Rostami-Hodjegan Amin 
Published: December 2015

In vivo derived ontogeny profiles for CYP1A2 and CYP3A4, show improved clearance (CL) predictions within a paediatric physiologically based pharmacokinetic (p-PBPK) model1. The aim of this study is to derive ontogeny functions (OF) for CYP2C9 and CYP2C19 based on age related CL data on ibuprofen and pantoprazole & lansoprazole, respectively.A literature review was undertaken to collect age related CL data for these probes, the values were deconvoluted back to intrinsic CL values (per mg of liver microsomal protein) as described previously. The 'best-fit' algorithm for ratio of paediatric to mean adult intrinsic CL with age was determined in Graphpad Prism5 to obtain in vivo OF for CYP2C9 and CYP2C19. These were compared for performance with previously established ‘in vitro' OF in Simcyp Paediatric simulator (v14) using validation datasets.CYP2C9 and CYP2C19 enzyme activities showed an increase with age to values higher than adults by ages 2 and 1 month respectively, maximum values were reached at 1.5 years and 6 months, respectively before declining to typical adult levels by around 25 years.The CYP2C9 in vivo derived OF led to improved predictions of diclofenac and S-Warfarin CL compared to in vitro derived OF across the age range. For CYP2C19 there is a dearth of suitable validation compounds due to lack of clinical data with a possibility of using omeprazole or voriconazole. The reasons for discrepancy between in vitro and in vivo derived OF require further investigation.
IMPLEMENTATION OF CLONIDINE AS A NEW SEDATIVE AND ANALGESIC DRUG IN THE NICU–A RETROSPECTIVE REPORT ON MEDICAL RECORDS
Authors: Ragnarsson Charlotte , Norman Elisabeth 
Published: December 2015

BackgroundAdequate pain relief is crucial for neonatal intensive care. Opioids are used despite their side effects. Clonidine has been introduced to reduce the opioid doses. Clonidine has never been studied in newborn infants.This study describes the strategy and the clinical response during a three year implementation period in a Swedish level-III NICU.MethodsThis is a retrospective study based on medical records, monitoring charts of physiological parameters and pain assessment, and Swedish national perinatal quality register data.Clonidine was administered to 97 patients and analyzed according to modes of intravenous administration (boluses and/or infusions). The indication, gestational and postnatal age at administration, doses, treatment duration, pain scoring, effects and concurrent medication were analyzed. Non-parametric statistics was performed (medians, IQR).ResultsThe infants were born at 28.6 (24.9–36.3) gestational weeks, birth weight 1058 (727–2660) g. The medication was introduced at postnatal age of 9 ((1–27) days. The maximum dosing was 1.4 microg/kg and 0.2 microg/kg/h for bolus doses and infusions, respectively, and the duration of exposure for the most common administration way (boluses followed by start of infusion) was 6 (3.8–11.5) days. The indication was sedation in 71%. Concurrent analgesics or sedatives, most commonly morphine, were given in 39% at start and 42% during the treatment period. The subjective effects were positive, and the side effects were few.ConclusionsOur study data support the benefits of clonidine with positive effects and few side effects. Pharmacokinetic and pharmacodynamics studies are needed in accordance with the FDA and EMA directives.
ACUTE POISONINGS IN A CHILDREN'S EMERGENCY DEPARTMENT
Authors: Starkey Elizabeth , Sammons Helen 
Published: December 2015

Objective To determine the incidence of children presenting to a children's emergency department with acute ingestion or poisoning. To identify common substances involved and those requiring admission and/or treatment.Method A retrospective notes survey was performed in children <16 years with a diagnosis of overdose or poisoning attending the local emergency department in 2013.ResultsA total of 441 events occurred with a potential diagnosis of overdose or poisoning in 428 children. This was 1.46% of all emergency attendances. 223 events (50%) were under 5 years with medicines or soaps and detergents being the commonest causes of accidental ingestion in 40% and 21% respectively. 182 events were over 12 years; 137 due to self-harm, 25 from alcohol and 9 from illicit drugs. 40% of all events required admission; 77% and 97% staying less than 24 and 48 hours respectively. In those staying over 2 days, only 1 patient remained for medical reasons requiring PICU care for a significant alcohol overdose. 10 patients received HDU care, 9 for close observation and 1 for treatment of recurrent seizures post mixed overdose. Only 2 patients had severe symptoms defined by the poisoning severity score.ConclusionAcute poisoning is a common reason to attend paediatric emergency departments. Most under 5 years don't require admission or treatment whereas over 12 years poisonings and overdoses are more problematic. Severe symptoms in children are rare suggesting further studies are required for determining the incidence of severe paediatric poisonings within the UK and Europe.
SEASONAL VARIATIONS IN ANTIBIOTIC CONSUMPTION IN PAEDIATRIC PRIMARY CARE SETTINGS IN SERBIA
Authors: Božić Bojana , Bajčetić Milica 
Published: December 2015

Background/ObjectiveAntibiotics are the most irrational prescribed drugs among the paediatric population. The aim of this study was to evaluate the seasonal variations in antibiotic prescribing profile among children in primary care settings in Serbia.MethodsPrescriptions of systemic antibiotics to the paediatric population (<18 years) for the period between 2011 and 2013 were analyzed by using the National Health Insurance Fund's outpatient reimbursement database.ResultsThe average number of antibiotic prescriptions was 1.887.615, while the average number of children receiving antibiotics was 728.285. The average annual rate was 1.394 antibiotic prescriptions per 1000 children. Significant differences in prescription rates in winter months compared to summer months were observed (t=5.51 p<0.001; t=2.29 p=0.045; t=3.65 p=0.004 for 95% confidence interval) during the followed up period. The average annual prevalence of antibiotic prescriptions was 54%. The most commonly prescribed antibiotics in paediatric population were amoxicillin, amoxicillin/clavulanic acid, cephalexin, azithromycin and erythromycin (90% of all prescribed antibiotics). The highest percentage of prescribed antibiotics was observed in the group of 2- to- 23- months-old children. Broad spectrum penicillins were the most prescribed antibiotics in all age groups, especially for children from 2–11 years of age, 51.92% (44.90%–57.13%), while the rate for cephalosporins was highest for children from 2–23 months, 30.91% (26.38%–36.44%), macrolides from 12 to 18 years, 22.67% (19.79%–26.05%) and quinolones from 0–1 month of age, 6.64% (5.09%–9.52%).ConclusionsSignificant seasonal variations in prescription practice and frequently used broad-spectrum antibiotics indicate that antibiotic prescribing is inappropriate.
LEGAL RESPONSIBILITY PRESCRIBING OFF-LABEL DRUGS: IS SPAIN DIFFERENT?
Authors: Peire Maria A. 
Published: December 2015

– In Spain the compassionate use and off-label prescription, are both regulated in the same law: the Royal Decree 1015/2009. This norm facilitates the access to drugs in specific clinical situations, similar to US regulation and in a different way to the UE regulation.– It is a legal practice to prescribe in an off-label manner if the following requirements are followed: there are no authorized therapeutic alternatives, prescribed in health centers, when access to these drugs is provided through a protocol of use after justifying (written) and properly informing (verbal) and obtaining the patient's consent.– When prescribing off-label the doctor's decision is based on contrasted scientific evidence (not merely on personal intuition nor personal experience). In fact, this anticipates an eventual update of the data sheet for new indications or populations, unlike the French situation where they have the ATU (Temporary Utilization Authorization).– In Spain the holder of the Marketing Authorization is obliged not to promote or advertise the use of the drug in different conditions to those approved (unlike the USA regulation).– The jurisprudential analysis from the Spanish Courts states that the doctor's responsibility is equal than that concerning on-label prescription, that is, only in the case of bad medical praxis (as in the USA). The most important cause of sentencing were: the lack of informed consent, lack of control of the medication and lack of correct follow-up of the illness, whereas this does not include the drug, dose, duration or even the patient's age.– In European Union the general rule dictated by the Courts is to permit off-label use if this is according to the best medical practice (lex artis ad hoc). Even more, there are some specific cases (in Germany, like in the USA) where it is possible to generate doctor's responsibility for no prescribing in a off-label manner.
A BLUE-PRINT FOR PERFORMING PAEDIATRIC PHARMACOLOGICAL RESEARCH
Authors: Vermeulen Eric , Nuytemans Debbie , de Haan Timo , Flint Robert , der Lee Johanna van 
Published: December 2015

IntroductionIn order to develop rational, patient tailored dosing schemes, population PK/PD studies in children and infants are needed. The emergence of new laboratory techniques (LC-MS/MS) and statistical tools (population PK/PD modeling) allows for the analysis of sparse and unbalanced data and has increased the possibilities to perform (observational) PK/PD studies in the paediatric clinic.To improve the quality of future pediatric PK/PD investigations the experience and knowledge about these tools should be shared and a basic study template agreed upon.ObjectiveWe aim to present a possible blue-print to assist paediatricians in the design and conduct of multicentre PK/PD studies in children and infants.MethodsBased on a review of the existing literature and multiple interviews with paediatricians and pharmacologists involved in multicenter paediatric PK/PD research a blue-print is drafted containing recommendations and examples for the design and implementation of PK/PD studies in children. The draft blue-print will be available at the conference and participants are asked for feed-back.ResultsPK/PD research to determine dosing in children and infants is preferably performed in a multi-center infrastructure in order to include a sufficient number of subjects within a reasonable time, covering all covariates relevant for dosage. The multi-center collaboration may also enable the analysis of multiple drugs in one cohort increasing cost-efficiency. Formal monitoring is needed to guarantee the quality of collected data.DiscussionIf performed well, the results of these studies will contribute to the evidence base underlying clinical guidelines and regulatory decisions concerning labeling adjustments.
NEW QUALITY INDICATORS FOR PAEDIATRIC ANTIBIOTIC PRESCRIBING IN PRIMARY CARE: A POPULATION BASED COHORT STUDY IN THE UNITED KINGDOM, ITALY AND THE NETHERLANDS FROM 1995–2010
Authors: Kaguelidou Florentia , de Bie Sandra , Verhamme Katia , de Ridder Maria , Picelli Gino , Strauś Sabine , Giaquinto Carlo , Stricker Bruno , Bielicki Julia , Sharland Mike , Sturkenboom Miriam 
Published: December 2015

BackgroundSuboptimal use of antibiotics may lead to antimicrobial resistance. The aim of this study was to develop and assess two new quality indicators (QIs) of optimal community-based prescribing applied to childhood community antibiotic (AB) prescribing in three European countries.MethodsA cohort study was conducted using electronic primary care medical records of 2,195,312 children up to 14 (Italy, Pedianet database, 2001–2010) or 18 years of age (UK, THIN database, 1995–2010; the Netherlands, IPCI database, 1996–2010) contributing for a total of 12,079,620 person-years (PYs). Prevalence rates of antibiotic prescribing were defined as the number of children with at least one antibiotic prescription per year and were expressed as the number of users per 100 PYs (%). Quality of prescribing was determined using four QIs: the drug utilisation 90% method, the ratio between users of broad and narrow spectrum penicillins, cephalosporins and macrolides (B/N ratio) and two new QMs: (i) the overall proportion of amoxicillin users (amoxicillin index, AI); (ii) the ratio between users of amoxicillin and those of broad spectrum antibiotics (the A/B ratio).ResultsThe overall annual prevalence of antibiotic prescriptions was 18% in the Netherlands, 36.2% in the UK and 52% in Italy. Prevalence was highest in the youngest children. Almost half of all prescriptions included amoxicillin with or without clavulanic acid. Cephalosporins were frequently prescribed in Italy. The AI provided trends for the utilization of a relatively narrow spectrum option targeting acute respiratory infections, and was highest in the Netherlands and in the UK (50–60%) and lower in Italy (30%), with a slight decrease over time in the UK and Italy. The overall B/N ratio varied between countries from 0.3 to 74.7, whereas the overall A/B ratio varied less from 0.5 in Italy to 6 in the UK, indicating a substantial proportion of narrower-spectrum prescribing in the UK.ConclusionsThe prevalence of antibiotic prescribing varied highly with age and country. A combination of total antibiotic prevalence and quality of prescribing based on amoxicillin use provide a clear picture of community childhood antibiotic prescribing. These measures could be used to evaluate the impact of programs aiming at reduction of AB use and appropriate antibiotic prescribing.
Comparison of clinical outcomes in patients with acute ischemic strokes treated with mechanical thrombectomy using either Solumbra or ADAPT techniques
Authors: Delgado Almandoz Josser E , Kayan Yasha , Young Mark L , Fease Jennifer L , Scholz Jill M , Milner Anna M , Hehr Timothy H , Roohani Pezhman , Mulder Maximilian , Tarrel Ronald M 
Published: December 2015

PurposeTo compare rates of symptomatic intracranial hemorrhage (SICH) and good clinical outcome at 90 days in patients with ischemic strokes from anterior circulation emergent large vessel occlusions (ELVO) treated with mechanical thrombectomy using either Solumbra or A Direct Aspiration first-Pass Thrombectomy (ADAPT) techniques.MethodsWe compared clinical characteristics, procedural variables, and clinical outcomes in patients with anterior circulation ELVOs treated with mechanical thrombectomy using either a Solumbra or ADAPT technique at our institution over a 38-month period. SICH was defined using the SITS-MOST criteria. A good clinical outcome was defined as a modified Rankin Scale score of 0–2 at 90 days.ResultsOne hundred patients were included, 55 in the Solumbra group and 45 in the ADAPT group. Patients in the ADAPT group had higher National Institutes of Health Stroke Scale (NIHSS) (19.2 vs 16.8, p=0.02) and a higher proportion of internal carotid artery terminus thrombi (42.2% vs 20%, p=0.03) than patients in the Solumbra group. Patients in the ADAPT group had a trend toward a lower rate of SICH than patients in the Solumbra group (2.2% vs 12.7%, p=0.07). Patients in the ADAPT group had a significantly higher rate of good clinical outcome at 90 days than patients in the Solumbra group (55.6% vs 30.9%, p=0.015). Use of the ADAPT technique (OR 6 (95% CI 1.0 to 31.2), p=0.049) was an independent predictor of a good clinical outcome at 90 days in our cohort.ConclusionsIn our cohort, the ADAPT technique was associated with significantly higher good clinical outcomes at 90 days in patients with acute ischemic stroke due to anterior circulation ELVOs treated with mechanical thrombectomy.
Transform margins of the Arctic: a synthesis and re-evaluation
Authors: Doré A. G. , Lundin E. R. , Gibbons A. , Sømme T. O. , Tørudbakken B. O. 
Published: December 2015

Abstract
Transform-margin development around the Arctic Ocean is a predictable geometric outcome of multi-stage spreading of a small, confined ocean under radically changing plate vectors. Recognition of several transform-margin stages in the development of the Arctic Ocean enables predictions to be made regarding tectonic styles and petroleum systems. The De Geer margin, connecting the Eurasia Basin (the younger Arctic Ocean) and the NE Atlantic during the Cenozoic, is the best known example. It is dextral, multi-component, features transtension and transpression, is implicated in microcontinent release, and thus bears close comparison with the Equatorial Shear Zone. In the older Arctic Ocean, the Amerasia Basin, Early Cretaceous counterclockwise rotation around a pole in the Canadian Mackenzie Delta was accommodated by a terminal transform. We argue on geometric grounds that this dislocation may have occurred at the Canada Basin margin rather than along the more distal Lomonosov Ridge, and review evidence that elements of the old transform margin were detached by the Makarov–Podvodnikov opening and accommodated within the Alpha–Mendeleev Ridge. More controversial is the proposal of transform along the Laptev–East Siberian margin. We regard an element of transform motion as the best solution to accommodating Eurasia and Makarov–Podvodnikov Basin opening, and have incorporated it into a three-stage plate kinematic model for Cretaceous–Cenozoic Arctic Ocean opening, involving the Canada Basin rotational opening at 125–80 Ma, the Makarov–Povodnikov Basin opening at 80–60 Ma normal to the previous motion and a Eurasia Basin stage from 55 Ma to present. We suggest that all three opening phases were accompanied by transform motion, with the right-lateral sense being dominant. The limited data along the Laptev–East Siberian margin are consistent with transform-margin geometry and kinematic indicators, and these ideas will be tested as more data become available over less explored parts of the Arctic, such as the Laptev–East Siberia–Chukchi margin.