bluuebunny/crossref_metadata_2025_split huggingface dataset:
PANTOPRAZOLE PHARMACOKINETICS IN OBESITY: WHERE GENES AND SIZE COLLIDE
Authors: Shakhnovich Valentina , Abdel-Rahman Susan , Friesen Craig , Pearce Robin , Gaedigk Andrea , Leeder J. Steven , Kearns Gregory 
Published: December 2015

BackgroundLimited dosing guidelines exist for overweight children (≈30% pediatric population). This prospective study examines the pharmacokinetics (PK) of pantoprazole (CYP2C19 substrate) in overweight vs. normal-weight children.MethodsUsing TaqMan techniques, 51 children (6–17 yrs) were genotyped for CYP2C19 loss-of-function (*2, *3, *4) and gain-of-function (*17) alleles. After a single oral dose of pantoprazole (1.2 mg/kg lean body weight), 10 plasma samples were collected over 8hrs, pantoprazole/metabolite concentrations measured by HPLC-UV, and PK parameters generated via non-compartmental methods. Using a two-tailed unpaired t-test, parameters were compared between overweight/obese (n=24) and normal-weight (n=25) children, and the effect of CYP2C19 genotype (*1/*1, n=24; *1/*17, n=15; *1/*2, n=7; *2/*17, n=3; *2/*2, n=2) on drug disposition was analyzed using a one-way ANOVA; α=0.05.ResultsDose-adjusted AUCtot, CL/F and other PK parameters were not significantly different between overweight/obese and normal-weight children. Independent of weight, mean AUCtot for pantoprazole was 2-fold greater in children with 1 loss-of-function vs. 1 gain-of-function allele (p=0.01). CL/F was increased only in children with *1/*17 genotype compared to all other genotypes (p<0.03), except *2/*17. In children with *1/*1 genotype (n=24), CL/F was significantly reduced (0.25±0.1 vs. 0.41±0.23 L/h/kg; p<0.05) and AUCtot increased (5.3±3.5 vs. 3.1±1.5 mg*h/L; p=0.05) in overweight/obese vs. normal-weight children. AUCtot was significantly increased in obese vs. normal-weight children (8.1±4.6 vs. 3.1±1.5 mg*h/L; p<0.05), with a positive correlation observed between AUCtot and BMI (r2=0.4; p=0.01).ConclusionsCYP2C19 genotype appears to be the primary determinant of pantoprazole PK in children, whereas BMI may explain individual variability within genotype groups.
AUGMENTED RENAL CLEARANCE IMPLIES A NEED FOR INCREASED AMOXICILLIN-CLAVULANATE DOSING IN CRITICALLY ILL CHILDREN
Authors: Cock Pieter De , Standing Joseph , Barker Charlotte , de Jaeger Annick , Carlier Mieke , Dhont Evelyn , Verstraete Alain , Delanghe Joris , Robays Hugo , Paepe Peter De 
Published: December 2015

BackgroundAmoxicillin/clavulanate is commonly used to treat community-acquired infections on the pediatric intensive care unit. Few data are available to guide dosing in this vulnerable population.MethodsThis prospective pharmacokinetic study enrolled patients admitted to the pediatric intensive care unit in whom intravenous amoxicillin-clavulanate was indicated (25–35 mg/kg q6h). Serial blood samples were obtained following the first and steady-state doses and amoxicillin/clavulanate concentrations were measured by a validated high-pressure liquid chromatography (HPLC)-tandem mass spectrometry method. Population pharmacokinetic analysis and Monte Carlo simulations were conducted using NONMEM’ 7.3.ResultsThree hundred twenty-five amoxicillin and 151 clavulanate blood samples were collected from 50 patients with a median age of 2.58 years (range: 0.08–15 years). A 3-compartment model for amoxicillin and a two-compartment model for clavulanate best described the data, in which allometric weight scaling and maturation functions were added a priori to scale for size and age. In addition, serum Cystatin C (sCysC) ‘as a marker for renal function’ and concomitant treatment with vasopressors were identified to have a significant influence on amoxicillin clearance. The typical population values of clearance for amoxicillin and clavulanate were 17.97 L/H/70 kg (95% CI:15.33–21.30 L/H/70 kg) and 12.20 L/H/70 kg (95% CI:10.54–14.55 L/H/70 kg), respectively. Four hourly dosing of 25 mg/kg (based on the amoxicillin component) was required to achieve 40% of the dosing interval for amoxicillin concentrations to be above MIC, and for clavulanate levels to be maintained above 2 mg/L. For patients with augmented renal function a 1 hour infusion was preferable to bolus dosing to achieve the therapeutic target.ConclusionsCurrent dosing regimens result in subtherapeutic concentrations in the early period of sepsis due to augmented renal clearance, which risks treatment failure in critically ill children.
POSSIBLE CONFOUNDERS IN THE REPORTED ASSOCIATION BETWEEN AUTISM SPECTRUM DISORDER (ASD) AND EXPOSURE TO SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS) DURING PREGNANCY
Authors: Bruyne Pauline De , Barzilay Eran , Koren Gideon 
Published: December 2015

BackgroundAutism has been in the forefront of public concern because of reported increase in prevalence and growing interest in the role of environmental risk factors in autism. A recent meta-analysis by Man et al. (2015) reported an increased risk of ASD in children of mothers exposed to SSRIs during pregnancy (adjusted OR 1.81, 95% CI 1.47–2.24). However, association may not imply a causal relation between SSRI exposure and ASD. We hypothesize that underlying disease might have confounded the published result.Materials and methodsA literature review was performed in order to identify possible confounders in the reported association. The list of search terms included but was not limited to following terms: ‘Pregnancy', ‘maternal', ‘depression', ‘child behaviour', ‘health care seeking behaviour'.ResultsRetrieved articles were classified in following four domains of possible confounders: 1/ direct link between depression and ASD, 2/effect of depression on interaction with the child, 3/effect of depression on other risk factors of ASD and 4/ascertainment bias. In the last domain, we examined the effect of depression on the way mothers perceive and report on the behaviour of their child and the effect of maternal depression on healthcare seeking behaviour. Analysis suggests that there are important merits to all those four domains.ConclusionBecause of obvious ethical reasons, research on exposure during pregnancy is mostly restricted to systematic review and meta-analysis of observational studies. Although this has resulted in a treasury of information, possible confounders must be taken into account when interpreting the results.
HEPATIC TRANSPORTER PROTEIN EXPRESSION IN FETUSES, NEONATES AND YOUNG INFANTS
Authors: Mooij Miriam , de Steeg Evita Van , Wortelboer Heleen , Vaes Wouter , Tibboel Dick , Wildt Saskia De 
Published: December 2015

BackgroundTransporters are membrane-bound proteins involved in trafficking substrates (e.g. drugs) across membranes of among others hepatocytes. Limited data exists on the developmental expression. We aim to study protein expression of transporters in fetal, neonatal and infantile liver.MethodsTransporter protein expression (ABCB1, ABCG2, ABCC2, ABCC3, BSEP, GLUT1, MCT1, OATP1B1, OATP2B1, OCTN2) was quantified using UPLC-MS-MS, on snap-frozen post mortem livers (Erasmus MC tissuebank) and adult control livers (UMC-Groningen). Protein expression was determined in isolated crude membrane and quantified using stable-isotope-labelled peptides. Age groups were compared with Mann-Whitney test and post hoc Bonferroni-correction (significance p<0.05). Data was compared to mRNA expression.Results25 liver samples were studied. 10 fetal [median gestational age 23.2 weeks (range 16.4–37.9)], 12 pediatric [postnatal age 1 week (0–11.4) and gestational age at birth 35.1 weeks (27.1–41.0)], and 3 adult liver samples. ABCB1, ABCC2, OATP1B1, OATP2B1 expressions appeared similar in fetuses, pediatrics and adults. MCT1 expression was similar in fetuses and adults, but higher in pediatrics. BSEP expression was lower in fetuses and pediatrics than in adults. ABCC3 expression was lower level in fetuses than in adults, but not in pediatrics compared to adults. ABCG2, GLUT1, OCTN2 expressions were higher in fetuses than in adults, but similar in pediatrics and adults.ConclusionHepatic transporters appear in different developmental expression profiles. ABCB1, ABCC2, OATP1B1 protein expression appears stable. This contrast previous mRNA expression data, which showed lower expression in fetus/neonate. The age-related differences in transporter expression may result in age-dependent pharmacokinetics of substrates.
DRUG PRESCRIPTION PROFILE AND PERINATAL DETERMINANTS DURING THE FIRST YEAR OF LIFE
Authors: Piovani Daniele , Clavenna Antonio , Pavoni Chiara , Bonati Maurizio 
Published: December 2015

The aim of the study was to investigate the drug prescription profile during the first year of life in a cohort of newborns, and the influence of perinatal and socio-demographic factors on drug prescription.A total of 61,479 neonates born in 2011 were included. The data source was the database of reimbursed prescriptions of the Lombardy region, Italy. Drug prescriptions were classified according to the Anatomical Therapeutic Chemical (ATC) classification system. Drug prevalence was calculated as the percentage of neonates receiving at least one drug prescription in one year. Chi-square test was used to compare prevalence of drug prescription in males and females.In all, 42,204 infants (68.7%) received at least one drug prescription, with a prevalence slightly higher in males than females (71.1% versus 66.1%; χ2=178 p<0.01). The drug classes most commonly prescribed in the first year of life were antibiotics (39.5% of infants), anti-asthmatics (32.6%), and corticosteroids for systemic use (9.8%).The median age of first prescription was 20.6 (Interquartile range: 9.4–33.3) weeks. Males received the first prescription about one week before females (20.1 versus 21.3, respectively). The first prescription concerned mainly anti-asthmatics (40.5%), and antibiotics (37.9%), and amoxicillin (16.3%), beclomethasone (16.0%), and amoxicillin+clavulanic acid (15.0%) were the most prescribed drugs.In conclusion, in the first year of life, 7 out of 10 infants received drug prescriptions. Males were more exposed than females, a finding consistent with the epidemiology of diseases in infancy. The analysis concerning the influence of maternal and perinatal factors is ongoing.
ALPROSTADIL ASSOCIATED FEVER IN THE NEWBORN: SIDE EFFECT OR INFECTION?
Authors: Swaid Sohair Bshara , Vardi Amir , Perlman Amichai , Matok Ilan 
Published: December 2015

BackgroundAlprostadil is a prostaglandin used to maintain patent ductus arteriosus in neonates with ductus arteriosus dependent congenital heart malformations. Alprostadil administration results in fever in ∼14% of treated neonates. The occurrence of fever in this setting, often leads to extensive investigations to identify the source of fever, as well as to empiric antibiotic therapy and the postponement of cardiac surgery. These measures can lead to several neonatal complications.AimTo identify clinical and laboratory criteria that can help determine the likelihood that fever during alprostadil therapy is due to infection.MethodsUsing a case control study design, we evaluated neonates who were admitted to the pediatric cardiac intensive care department between 2009 and 2014, and who developed fever during alprostadil treatment. Neonates with infection and without were compared to identify early clinical symptoms and biomarkers that can serve as predictors of infection. Analyses included univariate and multivariate methods.ResultsOur study included 124 neonates. Seventy neonates experienced infection (median age 9 days (IQR 4–15.2)) and fifty-four did not (median age 5 days (IQR 2–11)). Factors preceding fever and predicting infection included: White blood cell count (WBC) above 10000/microL (HR=1.97, 95% CI 1.02–3.74), or platelet count above 440 K/microL (HR=2.27, 95%CI=1.32–5.23). Increases in WBC or lactate, before fever onset, were also associated with infection.ConclusionsElevations in WBC, platelets and lactate before fever onset were associated with infection. These results may assist in decisions regarding cardiac surgery timing in neonates treated with alprostadil.
RISK FACTORS FOR NODAT UNDER IMMUNOSSUPPRESSANTS IN RENAL TRANSPLANTED CHILDREN
Authors: Lancia Pauline , Zhao Wei , Maisin Anne , Simon Dominique , Elie Veronique , Elie Valery , Jacqz-Aigrain Evelyne 
Published: December 2015

IntroductionNew Onset Diabetes After Transplantation (NODAT) is a major complication of immunossuppressive therapy and an risk factor for transplant rejection. Its incidence ranges from 4 to 25% in adults. In 2013, L. Elens and coworkers reported the association of two genetic variants PPARα rs4253728 and POR*28 rs1057868 with the occurrence of NODAT in renal transplanted adults treated with tacrolimus, MMF and corticosteroïds.ObjectiveOur objective was to assess the impact of these two genetics variants along with additional risk factors (age, sex, HLA missmatches…) on the occurrence of NODAT among renal transplanted children treated with tacrolimus, MMF, and corticoids.Materiel and methodGenotypes were determined using allelic discrimination technique. The univariate and mulivariate analyses have been performed using SPSS v15.Results238 renal transplanted children were identified between 1990 and 2013, 109 were treated with tacrolimus and included in the study (63 boys/46 girls). The mean age at time of transplantation was 10.8 years (±0.5) and mean duration of floow-up was 4 years (±0.3). A significant association of NODAT was evidenced with POR*28 (p=0.010) but not with PPARα (p=0.434), number of HLA mismatches (p=0.004) and donor's CMV serology (p=0.026).ConclusionThis pilot study validated the association between the SNP POR*28 and the occurrence of NODAT in renal transplanted children treated with tacrolimus. Early identification of patients carrying POR*28 genetic variant might allow to anticipate the risk of NODAT and improve patient's care.
PULMONARY HYPERTENSION IN PAEDIATRIC PATIENTS: DATA FROM THE COMPERA-KIDS REGISTRY
Authors: Gorenflo Matthias , Pittrow David , Huscher Dörte , Ziesenitz Victoria , Pattathu Joseph , Praus Alexander , Ewert Peter , Kaemmerer Harald , Group COMPERA-Kids Steering Committee Stu 
Published: December 2015

BackgroundPulmonary hypertension (PH/PAH) can have many possible causes in childhood. The aim of the COMPERA registry is the characterization of patients of all ages with PH/PAH and their treatment patterns.MethodsSince June 2013, paediatric patients can be included in the COMPERA registry (ClinTrials.gov: NCT01347216) which has originally been established for adult patients with pulmonary hypertension in 2007.ResultsUntil 2015, 78 patients <18 years (47 Pat <6 years) with pulmonary hypertension were enrolled, of whom 65.4% had PAH due to congenital heart disease (PAH-CHD), 25.6% had idiopathic PAH (iPAH), 3 had persistent PH of the newborn, 2 had PH associated with interstitial lung disease, and two had other PH. The patients were 6.1±6.0 years old, 52.6% girls; NYHA functional class I/II in 55.0%, and III in 42.3%. Mean disease duration after diagnosis was 37.7±55.8 months. Right heart catheterization data were available for 82.1% of the patients. Mean pulmonary artery pressure was 42.8±19.4 mmHg, right atrial pressure was 8.0±8.8 mmHg, cardiac index was 3.6±1.2 l/min/m2. Monotherapy was received by 65.4% of the patients whereas 33.4% of the patients had combination therapy. Phosphodiesterase-5 inhibitors (PDE5I) were administered to 76.9% of the patients, 35.9% of the patients received endothelin receptor antagonists and 3.8% received prostacyclins. About 24% of patients received anticoagulation therapy.ConclusionThe most common form of PH in this study cohort is PAH-CHD, followed by iPAH. Treatment options for children primarily comprise PDE5I. Only a small number of paediatric patients receive anticoagulation therapy.
RISKS IN PHARMACOLOGICAL TREATMENT OF PEDIATRIC INPATIENTS–THE DOCTORś AND NURSEŚ VIEWS
Authors: Lilja Lina , Garnemark Christiane , Kindblom Jenny 
Published: December 2015

BackgroundMedication errors in pediatric care are common and clinically important. The greatest risk of error occurs during drug prescription and administration of medicines. Medication errors can be prevented if potential sources of error are identified and addressed.ObjectiveExplore and describe the physicians' and nurses' views on the risks regarding pharmacological treatment of pediatric inpatients. Find out what the obstacles might be for the staff in their work with prescription, preparation and administration of medicines, and what might constitute help and improvements to reduce medical errors.MethodWe used three different methods to identify and describe the risks of pharmacological treatment at the department of pediatrics at Queen Silviás Children's Hospital in Gothenburg; reports from the medical error report system MedControl, targeted interviews with nurses and doctors and a questionnaire survey to all doctors and nurses.ResultsThe study revealed three main problem entities; difficulties related to drug prescription and the IT-system for computerized prescriptions, a need for improved support systems for drug prescriptions and administration as well as hazards relating to work environment such as disturbances, lack of time, and high staff turnover.ConclusionDrug treatment for children is a delicate matter that places high demands on everyone involved. A pressured work environment, incomplete IT systems and gaps in supports system for drug prescription and administration are unnecessary risks. To overcome these difficulties we propose extended local prescription and administration support, coordination of procedures between wards and development of IT systems adapted to the specific needs in pediatrics.
UNINTENTIONAL OVERDOSING OF INTRAVENOUS PARACETAMOL IN NEONATES: WHERE IS THE TOXICITY?
Authors: Bosch Barbara , Casteels Kristina , Allegaert Karel 
Published: December 2015

IntroductionParacetamol is a readily available antipyretic and analgesic, widely used to treat mild to moderate pain. Unintentional overdosing in neonates occurs, but so far only single case reports have been published. Based on an own case and a bibliographic search, we review the safety and tolerance of unintentiontal overdosing of intravenous paracetamol in neonates.Material and methodsA bibliographic search in PubMed and EMBASE using key words: “Pharmacokinetics paracetamol neonate”, “Metabolism paracetamol neonate” and “Effects paracetamol neonate” was performed.ResultsThirty cases of neonatal iv paracetamol intoxication were reported. Overall, the reported number remains limited, but even 10-fold drug errors only rarely result in significant morbidity or mortality. In accidental overdosing only one case of relevant hepatic toxicity has been reported.ConclusionThe reported cases of unintentional paracetamol overdosing in neonates suggests a good safety profile and a population specific tolerance. Acetylcysteine administration is recommended, but the prognosis seems to be better in neonates.
EXTENDED INTERVAL GENTAMICIN DOSING IN PRETERM INFANTS LESS THAN 35 WEEKS CORRECTED GESTATIONAL AGE
Authors: McKitrick Jarrid W R , Bewick Brad , Ariano Robert , Zelenitsky Sheryl , Narvey Michael , Jong Geert W 't 
Published: December 2015

ObjectiveTo confirm that gentamicin 5 mg/kg/dose every 48 hours in neonates less than 35 weeks corrected gestational age (CGA) results in the majority of gentamicin serum trough levels within the range of 0.5–2 mg/L and peak levels within the range of 6–12 mg/L.DesignProspective pharmacokinetic (PK) analysis.SettingTwo neonatal intensive care units and one intermediate care unit in two tertiary care centres. Patients: Neonates less than 35 weeks CGA who received empiric gentamicin for sepsis between March 10 and June 10, 2014 in whom at least one gentamicin serum level was measured. Methods: PK analysis was performed following implementation of empiric dosing for gentamicin of 5 mg/kg every 48 hours in neonates.ResultsMean Cl, t1/2 and V1 were 42±10 mL/kg/h, 10.0±1.8 h, and 0.58±0.09 L/kg, respectively (n=54). A one-compartment pharmacokinetic model best represented the data. The mean Cl of gentamicin at 24 h post dose was significantly lower in neonates.ConclusionsGentamicin 5 mg/kg q48h results in serum post dose levels between 6–12 mg/L 98% of the time compared to 5% of the time for once daily doses of 2.5 or 3 mg/kg. Gentamicin doses of 5 mg/kg q48h resulted in serum pre levels less than 0.5 mg/L 82% of the time (48 h post dose) compared to 9% of the time for once daily doses (24 h post dose). Increased clearance with advanced PNA suggests the need for more frequent dosing in neonates >14 days of age.
FLUOROQUINOLONES IN PEDIATRIC PATIENTS: NO MORE “OFF-LABEL USE”
Authors: Dinavitser Natalie , Berlin Maya , Miller Reuven , Finkel-Pekarsky Victoriya , Berkovitch Matitiahu 
Published: December 2015

Fluoroquinolones (FQs) are used in pediatric patients worldwide. However, due to cartilage damage in young animals they are not approved for children under 18 years of age for most indications. Major regulatory authorities such as EMA, FDA, UK, Ireland, NZ and Australia indicate that FQs are contraindicated in children. Ciprofloxacin and levofloxacin can be prescribed to children, but only for a few indications. As a result, FQs are used “off-label” in this population. From our experience, we believe that FQs should not be contraindicated in children. However, evidence-based data is needed.ObjectiveTo investigate whether FQ use in children may cause musculoskeletal adverse reactions (ADRs).MethodsWe reviewed the Israel Ministry of Health ADR reporting system and VigiLyze (WHO reporting system) for musculoskeletal ADRs due to FQs in children. A literature search– Medline, Pubmed, Cochraine database and pharmacologic textbooks, for musculoskeletal ADRs among FQ treated pediatric patients was conducted. Terms used: Fluoroquinolones, ciprofloxacin, levofloxacin, ofloxacin, arthropathy, tendinophaty, arthralgia, children, pediatric use.ResultsDuring the period 1968 to Feb 2015, the Israeli MOH did not receive spontaneous reports regarding FQs in children. The VigiLyze program identified 192 ADR reports in children related to FQs: arthralgia, arthropathy, myalgia, and tendon injury. Most ADRs were transient and reversible. The literature search indicated that although musculoskeletal ADRs are not uncommon, they are mild, transient, and not necessarily due to FQs. Joint MRI, performed in some of the studies, did not reveal cartilage damage.ConclusionsFQs should be registered for pediatric patients as for adults.