bluuebunny/crossref_metadata_2025_split huggingface dataset:
WHAT IS THE APPROPRIATE VALGANCICLOVIR DOSAGE IN CHILDREN WITH SOLID ORGAN TRANSPLANT? A PROSPECTIVE PHARMACOKINETIC STUDY
Authors: Peled Orit , Ashkenazi-Hoffnung Liat , Rom Eran , Bilavsky Efraim , Bernfeld Yael , Dorfman Lev , Amir Jacob , Brandriss Nurit , Bar-Haim Adina , Berkovitch Matitiahu 
Published: December 2015

Valganciclovir (VGC) is extensively used for cytomegalovirus (CMV) infection treatment and prophylaxis after solid organ transplantation (SOT). VGC dosing is problematic in children. VGC has variable absorption and is renally excreted. AUC0-24 of 40–60 mcg·h/L is a predictive pharmacokinetic parameter of efficacy and safety. Dosing based on manufacturer recommendations is supra-therapeutic in most cases. A few published dosing algorithms result in AUC out of range.ObjectiveTo prospectively validate a VGC administration dosing regimen and compare it to other dosing algorithms.MethodsChildren after SOT at Schneider Children's Medical Center, the largest tertiary pediatric center in Israel, were prospectively studied, starting Dec 2014. The dosing regimen was derived from Seattle Children's Hospital guidelines; 14–16 mg/kg/dose. For impaired renal function, stratified dose reduction was used. Blood was withdrawn at steady state: 2, 5 and 10 hours post dosing. Drug level was analyzed by HPLC.ResultsNine children aged 52 (37–137) [median; (inter-quartile range)] months were studied. Four had renal and 5 had liver transplantation. VGL dose administered was 16.67 (16.42–17.72) mg/kg/dose. AUC was 20.56 (18.7–22.7) mcg·h/L. AUC was sub-therapeutic in 8 children. Manufacturer-recommended dose in our patients was suppose to be 43.5 (24.84–46.7) mg/kg/dose, significantly higher than in our study (p=0.004). Dosing based upon Asberg et al study (Pediatr. Transplantation 2014;18:103) –25.5 (19.38–25.5) mg/kg/dose, was significantly higher than in our study (p=0.009).ConclusionsVGC dosing regimen in SOT children is still not clear. There are significant differences between dosing algorithms. More studies are needed. Recruitment of patients to our study continues.
EFFECT OF FLUSH VOLUME ON GENTAMICIN DELIVERY THROUGH UMBILICAL VENOUS CATHETERS
Authors: Lala Anita , Reith David , Broadbent Roland , Medilcott Natalie 
Published: December 2015

BackgroundIntravenous gentamicin is frequently prescribed for the treatment of early-onset sepsis to premature neonates. Background infusion rate and flush volume are known to influence gentamicin delivery and we aimed to further quantify these factors.MethodsIntravenous infusions were designed to simulate gentamicin delivery through umbilical venous catheters with a constant background flow rate of 0.5 mL/hr. Doses of gentamicin (2 mg or 5 mg) were administered by bolus injection over 3–5 minutes followed by a flush of 0.9% saline (1 mL or 2 mL). Samples were collected at 5 minute intervals for 1 hour and analysed by high pressure liquid chromatography.ResultsComplete recovery of 2 mg and 5 mg doses was observed following administration of both flush volumes. Of the 2.15 mg recovered when a 1 mL flush is used, 85% (standard deviation, SD, 3.1%) was collected by 10 minutes and 93% (SD 1.4%) over the first 30 minutes. When a 2 mL flush is given, 99% (SD 0.5%) of the 1.88 mg administered dose is recovered in 10 minutes. Following a 5 mg intended dose, 93% (SD 3.4%) is recovered at 10 minutes and 97% (SD 2%) in 30 minutes after a 1 mL flush, compared to 99% (SD 0.6%) recovery at 10 minutes with a 2 mL flush.ConclusionSimulated gentamicin delivery by bolus injection into slow-flowing neonatal central lines resulted in >90% dose recovery at 1 hour. Additionally, discrepancies between intended and actual gentamicin dose, and retrograde flow of dye was observed.
SPONTANEOUS ADVERSE DRUG REACTION REPORTS FOR TRANSPLACENTAL AND TRANSMAMMARY ROUTES IN THOSE ≤1 YEAR IN THE UK 2001–2010
Authors: Russell Nicki-Jayne , Turner Mark , Hawcutt Dan 
Published: December 2015

AimsThe UK Medicines and Healthcare products Regulatory Agency (MHRA) runs a national spontaneous reporting system (Yellow Card Scheme, YCS) to collect suspected adverse drug reaction (ADR) data. We describe the Yellow card reports received for patients aged ≤1 year across a 10 year period (2001–10).MethodsThe MHRA supplied YCS data for patients aged ≤1 year from the years 2001–2010. This analysis includes all reports involving transplacental, transmammary, or paternal route of exposure. Data were analysed to include number, type and outcome of ADRs.ResultsThere were 279 reports, including 249 different medications (a YCS may contain ≥1 medication). The most commonly reported drugs were fluoxetine (n=25), citalopram (n=22), paroxetine (n=19) and venlafaxine (n=19). The outcome of the ADR was death in 10.4% of reports. Doctors reported 75.4% (n=215) of reports, however only 3.9% (n=11) were from the parent/carer. Gender was documented in 66% cases and gestation was stated in only 15% of reports.ConclusionsDespite many women requiring medications in pregnancy and while lactating, very few YCS reports were received over a 10 year period. Current MHRA advice is for all suspected ADRs in children following transplacental or transmammary exposure to be reported. Strategies to improve reporting in this neglected population are urgently needed.
MIDAZOLAM FOR IMAGING PROCEDURAL SEDATION IN CHILDREN: A SYSTEMATIC REVIEW
Authors: Alotaibi Badriyah , Choonara Imti , Sammons Helen 
Published: December 2015

AimTo evaluate effectiveness and safety of midazolam as a sedative agent in children undergoing imaging procedures.MethodsA systematic literature review on MEDLINE (1948–September 2014), EMBASE (1980–September 2014), International Pharmaceutical Abstracts (1970 to September 2014) and PubMed database (until September 2014) in all languages. Studies evaluating midazolam use in children undergoing imaging procedural sedation were included if they reported efficacy and/or safety outcomes.Results25 studies, in 6145 patients, evaluated adverse events (AEs). Dosage and route ranged from 0.1 to 0.6 mg/kg for intravenous route, 0.15 to 0.45 mg/kg for intranasal, 0.5 to 0.6 mg/kg for oral and 0.3 to 1 mg/kg for rectal administration. The most common AE was hypoxia (74), in 3.6 per 100 patients. Cases were mild (SpO2 90–95%) in 42 (2.1% incidence) and moderate (SpO2<90%) in 32 cases (1.5%), with no severe cases. All were completely reversible after simple airway manoeuvres. Vomiting was the second most frequently, 1 per 100 patients. Two serious AEs occurred, both myoclonic-like movements of upper and lower extremities requiring medical interventions and hospitalisation. 24 studies, in 3717 patients, evaluated efficacy. Procedural success rates ranged from 0% to 100%, median 86%. Success was higher for shorter procedures; CT scan (median 86.7%) versus for MRI (median 59%).ConclusionsMidazolam for imaging procedural sedation has a low incidence of AEs, the occurrence of hypoxia emphasises the importance of monitoring during sedation. The success rate is variable, with shorter procedures seeing better results.
SHORT-COURSE ORAL CORTICOSTEROID TOXICITY IN CHILDREN
Authors: Ajebab Fahad , Choonara Imti , Conroy Sharon 
Published: December 2015

BackgroundMultiple studies have evaluated and reported adverse drug reactions (ADRs) of corticosteroids. Short course oral corticosteroids are commonly used in children in the management of conditions such as asthma exacerbations. This systematic review aimed to identify the most common and serious ADRs associated with short courses of oral corticosteroids and to determine their relative risk levels in children.MethodsA literature search of the databases: Embase, Medline, International Pharmaceutical Abstracts, CINAHL, the Cochrane Library and PubMed was performed to identify all studies where corticosteroids had been administered to paediatric patients ranging from 28 days to 18 years of age for up to and including 14 days of treatment. Each database was searched from their earliest dates to December 2013. All types of studies that provided clear information on adverse events were included with no language restrictions. Quality assessments were performed on all studies by two independent reviewers.ResultsThirty eight studies met the inclusion criteria. These studies represented 3202 children and contained reports of 847 adverse events. The three most frequent ADRs were vomiting, increased blood pressure and behavioural changes. The incidence rates of these three ADRs were 6.3%, 8.5% and 4.8% of patients respectively. The risk of vomiting was greater with oral prednisolone than oral dexamethasone with a relative risk of 3.62 (95% CI 1.89, 6.95; P=0.0001). Prednisolone sodium phosphate was reported to cause vomiting less frequently than other prednisolone dosage forms (P=0.047). HPA axis suppression was detected in 43 of 53 patients who were tested. The relative risk of oral prednisolone to cause HPA axis suppression compared with inhaled steroids was 9.95 (95% CI 1.73, 53.03; P=0.010). Infection was one of the most serious ADRs, one child died after contracting a varicella zoster infection.ConclusionsVomiting, increased blood pressure and behavioural changes were the most frequent ADRs seen when short-course oral corticosteroids were given to children. In addition, infection was the most serious ADR. The majority of children who receive short course oral corticosteroids will experience HPA axis suppression.
HOW DOES THE IN VIVO BILIARY ELIMINATION OF DRUGS CHANGE WITH AGE? EVIDENCE FROM CLINICAL DATA USING A SYSTEMS PHARMACOLOGY APPROACH
Authors: Johnson Trevor , Rowland-Yeo Karen , Jamei Masoud , Rostami-Hodjegan Amin 
Published: December 2015

There is little information on the development of biliary drug elimination (BE) with age. The aims of this study were to collate literature data on the pharmacokinetics of biliary excreted drugs used in paediatrics and to apply a Physiologically Based Pharmacokinetic model to predict their systemic clearance (CLiv) across this age range.Drug parameters for azithromycin, ceftriaxone and digoxin were collated from the literature and validated against adult clinical data in Simcyp (V14R1). The change in CLiv with age was simulated in the paediatric model and compared to the observed data; the ontogeny function associated with BE was optimised in order to recover the age-related CLiv.For azithromycin (79% BE) a fraction of adult biliary excretion activity of 15% had to be assumed to be able to predict accurately the CL of the drug in neonates (24 to 28 weeks GA) whilst 100% activity was apparent by 7 months. For ceftriaxone (51% BE) full biliary excretion activity appeared to be present at full term birth. Finally, for digoxin (25% BE), a fraction of adult biliary excretion activity of 10% had to be assumed to predict the CL of the drug at birth whilst 100% activity was present by The ontogeny of BE for all three drugs appears to be rapid and reach adult levels at birth or in the first few months of postnatal age. More research is required in this area particularly on the ontogeny of specific canalicular transporters in humans.
POPULATION PHARMACOKINETICS AND DOSING OPTIMIZATION OF TEICOPLANIN IN CHILDREN WITH MALIGNANT HAEMATOLOGICAL DISEASE
Authors: Zhao Wei , Zhang Daolun , Storme Thomas , Baruchel André , Declèves Xavier , Jacqz-Aigrain Evelyne 
Published: December 2015

BackgroundChildren with haematological malignancy represent an identified subgroup of the paediatric population with specific pharmacokinetic parameters. In these patients, inadequate empirical antibacterial therapy may result in infection-related morbidity and increased mortality, making optimization of the dosing regimen essential. As paediatric data are limited, our aim was to evaluate the population pharmacokinetics of teicoplanin in order to define the appropriate dosing regimen in this high-risk population.MethodsThe current dose of teicoplanin was evaluated in children with haematological malignancy. Population pharmacokinetics of teicoplanin was analysed using NONMEM software. The dosing regimen was optimised based on the final model.ResultsEighty-five children (age range: 0.5 to 16.9 years) were included. Therapeutic drug monitoring and opportunistic samples (n=143) were available for analysis. With the current recommended dose of 10 mg/kg/day, 41 children (48%) had sub-therapeutic steady-state trough concentrations (Css,min<10 mg/liter). A two-compartment pharmacokinetic model with first-order elimination was developed. Systematic covariate analysis identified that bodyweight (size) and creatinine clearance significantly influenced teicoplanin clearance. The model was validated internally. Its predictive performance was further confirmed in an external validation. In order to reach the target AUC of 750 mg·h/L, 18 mg/kg was required for infants, 14 mg/kg for children and 12 mg/kg for adolescents. A patient-tailored dose regimen was further developed and reduced variability in AUC and Css,min values compared to the mg/kg-basis dose, making the modelling approach an important tool for dosing individualization.ConclusionsThis first population pharmacokinetic study of teicoplanin in children with haematological malignancy provided evidence-based support to individualize teicoplanin therapy in this vulnerable population.
PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS FOR ADULT AND PAEDIATRIC CHRONIC HEART FAILURE PATIENTS USING THE EXAMPLE OF CARVEDILOL TREATED PATIENTS
Authors: Rasool Muhammad , Khalil Feras , Läer Stephanie 
Published: December 2015

BackgroundIn chronic heart failure (CHF), the changes in organ blood flows can significantly affect the metabolism of drugs with high hepatic extraction. Physiologically based pharmacokinetic modelling (PBPK) can be utilized to predict clearances of high extraction drugs like carvedilol in CHF. The adult PBPK-CHF model after its evaluation in adults, can be scaled to pediatrics using population based PBPK simulator.MethodsAfter a literature search for model input parameters, two-PBPK models were developed which differed only on the basis of clearance as, model-1 was based on human liver and intestinal microsomes clearance and model-2 was based on cytochrome-P450 clearances. Developed models were evaluated in healthy adults and in adult CHF patients, after incorporation of reduced organ blood flows. The evaluated adult CHF models were finally scaled to pediatric CHF patients using population based simulator Simcyp®. A two-fold error range for the ratios(Obs/Pred) of the pharmacokinetic parameters was used for model evaluation.ResultsThe prediction results from both models were within the 2-fold error range but the initial absorption phase after oral drug application was slightly over predicted with model-1 on the other hand, the model-2 efficiently captured the oral absorption phase. The CL/F ratios(Obs/Pred) were clearly improved after incorporation of reduced organ blood flows in adult CHF patients. In pediatrics CHF patients, improvement in predictions were seen only in adolescents above 17 years of age, staged with NYHA system of classification.ConclusionThere was a clear link between reduced organ blood flows and reduced carvedilol clearance in adult patients with CHF. It was suggested that Ross scoring system in pediatrics was not well correlated with organ blood flow reductions as the NYHA classification system. Due to the mechanistic nature of the developed models, they can be extended to other drugs with high hepatic extraction.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) and from the Faculty Development Program BZ University Multan, Pakistan.
INVASIVENESS OF PHARMACOKINETIC STUDIES IN CHILDREN–A SYSTEMATIC REVIEW
Authors: Altamimi Mohammed , Sammons Helen , Choonara Imti 
Published: December 2015

ObjectivesTo compare the invasiveness of recent pharmacokinetic (PK) studies with older studies. The extent of this will be evaluated by analysing the number of samples and volume of blood collected in each study.MethodsA systematic literature review was performed to identify papers describing number of samples and volume of blood collected in studies of children (aged 0–18 years). The following databases were searched: Medline (1946 to May 2014), Embase (1974 to May 2014), International Pharmaceutical Abstracts (1970 to May 2014), CINAHL and Cochrane library. The keywords were “preterm neonate*” OR term neonate*” OR “neonate*” OR “new-born*” OR “child*” OR children OR “p*ediatric* OR “infant*” OR “adolescent*” AND “pharmacokinetic*” OR blood OR plasma OR specimen OR serum OR blood sampling OR blood sample*. Patients were grouped according to the guidelines of the International Conference of Harmonization (ICH), i.e. preterm neonates, term neonates, infants (28 days-under 2 years), children (2–11 years) and adolescents (12−≤18 years).ResultsA total of 501 paediatric PK studies were identified between 1974 and 2014. Eighty eight studies were conducted between 1980 and 1990 (old studies), while 193 were conducted between 2004 and 2014 (new studies). Significantly more blood samples per child were collected in the old (median 8 [IQR: 6–11]) versus the new studies (median 7 [IQR: 5–9]) (p=0.002). In children the frequency of blood sampling was significantly higher in old studies (median 9 [IQR: 7–12]) compared to new studies (p=0.0002), but in the other age categories, there were no significant differences. There was no significant difference in the individual sample volume collected at each time point between two periods (p=0.913). However the total volume of blood collected for the study was significantly more in the old period (median=14 ml IQR [4.5–27.5 ml]) than in the new studies (median=11 ml, IQR [6–18 ml]) (p=0.040).ConclusionsSignificantly more blood samples and larger total volumes of blood were taken in the old studies compared to new PK studies involving children. No major difference in the individual sample volume was seen.
AVAILABILITY OF PAEDIATRIC-EVALUATED FORMULATIONS IN SERBIA
Authors: Božić Bojana , Stupar Sanja , Stupar Duško , Bajčetić Milica 
Published: December 2015

Background/ObjectiveA lack of appropriately evaluated medicines for paediatric population is a major problem as it often leads to inadequate treatment of children. The aim of this study was to investigate the availability of paediatric formulations labelled for children up to the age of 12 years old in Serbia in 2013, as well as the availability of paediatric medicines reimbursed by the Republic Health Insurance Fund (RFZO). The availability of paediatric formulations in Serbia is also compared with the ‘Model List of Essential Medicines for Children’ by World Health Organization's (WHO).MethodsSources of information about medicines were: the Summary of Product Characteristics (SmPc), RFZO Drug Lists, WHO Model Lists of Essential Medicines for Children, and Serbia's official drug registry, editions 2013.ResultsIn Serbia only 49% (496) of INN drugs were suitable for children of which only 66% were licensed for paediatric use. Majority of licensed drugs were parenteral formulations, 57%, followed by drugs for local use, 28%, and formulations for oral use, 23%. The lowest availability of medicines was for children 0–27 days old. From the total number of licensed medicines for children up to 12 years old, the Republic Fund for Health Insurance covers 64% of drugs and from each therapeutic group at least one medicine is reimbursed by fund. The availability of WHO essential medicines for children in Serbia was 51%, from which 92% were licensed for paediatric use.ConclusionOur study showed that from already unsatisfactory number of available drugs for children only 66% is licensed. Limited availability of paediatric medicines for all ages of this population and for a broad range of therapeutic areas still represents a cause for concern in our country.
RANDOMISED CONTROLLED TRIALS OF CHRONIC PAIN IN CHILDREN AND ADOLESCENTS: A SYSTEMATIC REVIEW
Authors: Boulkedid Rym , Abdou Armiya Yousouf , Desselas Emilie , Monegat Marlène , Alberti Corinne , Kaguelidou Florentia 
Published: December 2015

BackgroundApproximately 15 to 30% of children and adolescents suffer from daily pain persistent over more than 3 months and there is evidence supporting that the prevalence of chronic pain is steadily increasing in this population. Chronic pain is known to have a negative impact on children's development and social behaviour, leading often to severe psychological distress and physical disability. We reviewed medical literature to assess the characteristics and quality of randomized controlled trials (RCTs) on pharmacological and non-pharmacological therapies in chronic and recurrent pain in the paediatric population.MethodsWe performed a systematic search of PubMed, Embase and the Cochrane Library up to March 2014. Bibliographies of relevant articles were also hand-searched. We included all RCTs that involved children and adolescents (age 0 to 18 years) and evaluated the use of a pharmacological agent or a non-pharmacological approach in the context of chronic or recurrent pain. The latter was defined as pain persisting for more than 3 months. Methodological quality was evaluated using the Cochrane Risk of Bias Tool. Two reviewers independently assessed studies for inclusion and evaluated methodological quality.ResultsA total of 52 randomized controlled trials were selected and included in the analysis. The majority were conducted in single hospital institutions, with no information on study funding. Median sample size was 45 (34–57) participants. Almost 50% of the RCTs included both adults and children with a median age at inclusion of 13 years. Non-pharmacological approaches were more commonly tested whereas evaluation of pharmacological agents concerned less than 30% of RCTs. Abdominal pain and headache were the most common types of chronic pain experienced among trial participants. Overall, the methodological quality was poor and did not parallel the number of RCTs that increased over the years. The risk of bias was high or unclear in 70% of the trials.ConclusionsThis is the first systematic review of RCTs conducted to evaluate pharmacological and non-pharmacological therapies in chronic and recurrent pain in children and adolescents. Although, management of pain in adults has significantly improved over the years due to the evaluation of numerous analgesic therapies, our results highlight the existing knowledge gap with regards to children and adolescents. Therapeutic strategies, in particular pharmacological agents, applied to relieve chronic or recurrent pain in children and adolescents are not evaluated through high quality RCTs. The need to improve analgesic therapy in children and adolescents with chronic pain is still unmet. We discuss possible research constraints and challenges related to this fact as well as adequate methodologies to circumvent them.