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Aims: The pharmacokinetics (PK) of fluconazole and micafungin differ in neonates compared with children and adults. Dosing instructions in product labels appear to be inconsistent with the emerging scientific evidence. Limited information is available on the safety profile of these agents in neonates. Our objective was to study the population PK and safety of both drugs, randomly administered in neonates with suspected or confirmed systemic candidiasis. Methods: Neonates were randomized 1:1 to fluconazole (loading dose 25 mg kg–1; maintenance dose 12 mg kg–1 day–1 or 20 mg kg–1 day–1, respectively, for infants <30 weeks or ≥30 weeks’ corrected gestational age) or micafungin (loading dose 15 mg kg–1 day–1; maintenance dose 10 mg kg–1 day–1). PK samples were taken on treatment days 1 and 5. Population parameters were determined using NONMEM and Monte Carlo simulations performed to reach predefined targets. Clinical and laboratory data, and adverse events were collected up to 36 weeks’ corrected gestational age or hospital discharge. Results: Thirty‐six neonates were enrolled. The median (range) gestational age was 28.2 (24.1–40.1) and 26.8 (23.5–40.0) weeks for fluconazole and micafungin, respectively. Based on 163 PK samples, the median population clearance (l h–1 kg–1) and volume of distribution (l kg–1) for fluconazole were: 0.015 [95% confidence interval (CI) 0.008, 0.039] and 0.913, and for micafungin were: 0.020 (95% CI 0.010, 0.023) and 0.354 (95% CI 0.225, 0.482), respectively. The loading dose was well tolerated. No adverse events associated with micafungin or fluconazole were reported. Conclusion: Based on Monte Carlo simulations, a loading dose for fluconazole and dosing higher than recommended for both drugs are required to increase the area under the plasma drug concentration–time curve target attainment rate in neonates. [ABSTRACT FROM AUTHOR]

Background/Objective:To determine gastrointestinal (GI) responses and maximum tolerated dose of erythritol in young children given as a single oral dose in a 250-ml non-carbonated fruit-flavoured beverage in between meals. This is a multicentre double-blind study with sequential design for multiple dose groups and randomised crossover for comparators of placebo vs dose.Subjects/Methods:A total of 185 healthy young children aged 4-6 years were recruited at three clinical investigation centres after informed consent of both parents; 184 children completed the study. Children were included in one of the four dose groups (5, 15, 20 or 25 g erythritol) and exposed randomly to only one single dose vs an isosweet sucrose placebo. After consumption in the clinic and an observation period, GI symptoms and stooling patterns were recorded during the next 48 h.Results:Statistically significantly more episodes of diarrhoea and/or severe GI symptoms were observed in the 20 and 25 g groups compared with placebo, but not in the 5 and 15 g groups. Stool consistency, as measured by Bristol stool scale, was lower in the 15-, 20- and 25 g groups for the first 24 -h period, but not at later time points. Incidences of nausea, vomiting, borborygmi, excess flatus and abdominal pain were not significantly different from the placebo controls at all doses of erythritol.Conclusions:Rapid ingestion of up to and including 15 g (6% w/v) of erythritol in a beverage in between meals by young children aged 4-6 years was well tolerated. The no observed effect level for diarrhoea and/or severe GI symptoms was 15 g (0.73 g/kg body weight (bw)). Children appeared not to be more sensitive to the GI effects of erythritol than published for adults on a g/kg bw basis. [ABSTRACT FROM AUTHOR]

Nonsteroidal anti-inflammatory drugs (NSAIDs) possess antipyretic, analgesic and anti-inflammatory effects. They are frequently used in children and have numerous therapeutic indications, the most common ones being fever, postoperative pain and inflammatory disorders, such as juvenile idiopathic arthritis (JIA) and Kawasaki disease. Their major mechanism of action is through inhibition of prostaglandin biosynthesis by blockade of cyclo-oxygenase (COX). The disposition of most NSAIDs has been mainly studied in infants ≥2 years of age. Compared with adults, the volume of distribution and clearance of NSAIDs such as diclofenac, ibuprofen (infants aged between 3 months and 2.5 years), ketorolac and nimesulide were increased in children. The elimination half-life was similar in children to that in adults. These pharmacokinetic differences might be clinically significant with the need for higher loading and/or maintenance doses in children. Ibuprofen, acetylsalicylic acid (ASA) and acetaminophen are the most frequently used agents for fever reduction in children. Over the past 20 years, because of the association between ASA use and Reye's syndrome, most of the interest has been directed toward ibuprofen and acetaminophen. In view of its comparable antipyretic efficacy, but superior tolerability profile, acetaminophen, when used appropriately with age-adapted formulations, should remain the first-line therapy in the treatment of childhood fever. At the moment, there is no scientific evidence to recommend simultaneous use of these two antipyretic drugs. Most NSAIDs provide mild to moderate analgesia, with the exception of ketorolac which has a strong analgesic activity. The analgesic efficacy of ketorolac, ketoprofen, diclofenac and ibuprofen in the treatment of postoperative pain has been mainly studied following a single dose, in children of ≥1 year of age undergoing minor surgeries. In this setting, when used either alone or in adjunct to caudal or epidural anaesthesia, they were associated with an opioid-sparing effect and were well tolerated. With the exception of ketorolac use in children undergoing tonsillectomy, where controversy exists regarding the risk of postoperative haemorrhage, NSAIDs have not been associated with an increased risk of perioperative bleeding. NSAIDs are the first-line therapy in JIA. They appear to be equally effective and tolerated, with the exception of ASA which is associated with more adverse effects. ASA has been used for many years in the treatment of Kawasaki disease and is part of the standard modality of treatment in combination with intravenous gammaglobulins. More recently, lung inflammation associated with cystic fibrosis (CF) has become a new target for NSAIDs. Despite promising preliminary results with ibuprofen, numerous questions need to be answered before this new strategy becomes part of the conventional treatment of patients with CF. In summary, NSAIDs are effective in reducing fever, alleviating pain and reducing inflammation in children, with a good tolerance profile. Pharmacokinetic studies are needed to characterise the disposition of NSAIDs in very young infants in order to use them rationally. To date, no studies have been published on the disposition, tolerability and efficacy of specific COX-2 inhibitors in children. Further clinical experience with these agents in adults is warranted before undergoing trials with specific COX-2 inhibitors in children. [ABSTRACT FROM AUTHOR]

Mycophenolate mofetil (MMF) is a prodrug that is hydrolyzed to the active immunosuppressant mycophenolic acid (MPA). The drug is now widely prescribed for adult renal transplant recipients and its use has been extended to pediatric patients, although pharmacological data in this age group are limited. Nine pediatric renal transplant recipients received MMF with corticosteroids and either cyclosporine or tacrolimus a median of 55 months (range 7.5–124 months) months after transplantation. The pharmacokinetic parameters of MPA and MPA glucuronide (MPAG) were determined at steady state by high-performance liquid chromatography after administration of MMF at the oral dose of 494±142 mg/m[sup 2] twice daily. MPA was rapidly absorbed, with a peak concentration at 1.4 h. The mean plasma concentration of MPA at steady state was 4.7±1.3 µg/ml. The areas under the plasma concentration-time curves (AUCs) over 12 h (between two administrations) were 57.0±15.3 µg.h/ml for MPA and 1,515±722 µg.h/ml for MPAG, and the apparent oral clearance was 11.7±7.0 and 0.5±0.4 l/h for MPA and MPAG, respectively. Assuming that the pharmacokinetics of MPA was dose dependent, the mean concentration at steady state and the AUC for MPA were calculated for the recommended dosage schedule of 600 mg/m[sup 2] every 12 h and were 6.3±2.7 µg/ml and 75.2±32.9 µg.h/ml, respectively. The tolerance of MMF was studied prospectively with a follow-up of 1.1±0.2 years. Gastrointestinal disorders requiring dosage reduction or discontinuation of therapy, observed in five of nine patients, occurred at an incidence higher than expected from adult data. Our results suggest that the dose of 600 mg/m[sup 2] every 12 h extrapolated from adult data for use in pediatric patients would be associated with plasma levels and AUCs higher than expected and may be associated with a higher incidence of side-effects, primarily gastrointestinal. [ABSTRACT FROM AUTHOR]

Evaluates the efficacy and safety of midazolam in critically ill newborn babies through a randomized, double-blind and placebo-controlled trial. Basis of drug doses; Assessment of behavior changes; Comparison of the sedative effect of midazolam with placebo; Incidence of respiratory distress syndrome.

: ObjectiveConflicting data have been reported in the association between maternal smoking and adverse effects during pregnancy and in neonates. Some studies, conducted on a limited number of patients have evaluated maternal consumption and fetal exposure by measuring nicotine and cotinine in the hair. Our aims were to evaluate the relationship among maternal cigarette consumption, fetal smoking exposure and outcome of pregnancy in a population of pregnant women who smoked.: DesignMothers smoking during pregnancy were included at their first prenatal visit and followed prospectively. Maternal data (demographic variables, obstetrical history and cigarette consumption), neonatal data and birth indicators (number of weeks of gestation, type of delivery, weight) were collected. Hair samples from the mothers and the babies were collected at birth.: SettingThe present study was conducted in the Department of Obstetrics of the University Hospital Robert Debre´ in Paris.: PopulationA total of 254 women smokers were included in the study and 182 mother/neonate pairs were analyzed after exclusion of 50 babies whose hair samples were inadequate and 22 for various other reasons.: MethodsNicotine and cotinine concentrations in the maternal and neonatal hair were measured at birth by radio-immunoassay.: Main outcome measuresCigarette consumption was based on self reporting and quantified each trimester. It was expressed more precisely during the third trimester by the mean number per cigarette per day. Nicotine and cotinine concentrations in the maternal and neonatal hair at birth were also analysed.: ResultsNicotine and cotinine concentrations in maternal hair were associated with cigarette consumption during the third trimester of pregnancy (P < 0.003 and P < 0.01, respectively). In neonates, only cotinine concentrations were associated to maternal cigarette consumption (P < 0.0001). This association remained significant in a multivariate analysis, which included maternal cotinine hair concentrations and the ethnic group.: ConclusionsOur results have shown a strong relationship between maternal cigarette consumption and fetal exposure to smoking measured by cotinine concentrations in neonatal hair. Further studies are required to look for associations between fetal exposure and adverse pregnancy outcome. [Copyright &y& Elsevier]

Purpose To study efficacy and tolerance of ophthalmic insert Mydriasert® versus standard treatment phenylephrine and tropicamide eye drops for fundus examination in neonates. Methods Prospective, randomised, single-blinded non-inferiority study of 80 premature and full-term babies and infants treated for fundus examination. Mydriasis was obtained with two groups randomly assigned. The eye drop group received three instillations of 2.5% phenylephrine and 0.5% tropicamide and the insert group received Mydriasert® containing phenylephrine and tropicamide. the mydriasis was evaluated 75 minutes after the introduction of the mydriatic agents. Results The mydriasis was successfully achieved in both eyes in 97.5% of infants in the insert group and 90% in the eye drop group at 75 minutes after dispensation. The efficacy of the insert was non-inferior compared to the eye drops. To reach effective mydriasis, the insert group required fewer nursing interventions for one patient comparing to the eye drop group. Good general and local tolerance was observed in the two groups. However two patients reported an adverse event as bradycardia and gastro-oesophageal reflux that could be related to neonate pathology. Conclusions Mydriasis obtained with the ophthalmic insert Mydriasert® was not inferior compared to standard eye drop treatment. Insert reduced the number of nursing interventions to obtain mydriasis for a fundus examination. [ABSTRACT FROM AUTHOR]

Purpose To study efficacy and tolerance of ophthalmic insert Mydriasert® versus standard treatment phenylephrine and tropicamide eye drops for fundus examination in neonates. Methods Prospective, randomised, single-blinded non-inferiority study of 80 premature and full-term babies and infants treated for fundus examination. Mydriasis was obtained with two groups randomly assigned. The eye drop group received three instillations of 2.5% phenylephrine and 0.5% tropicamide and the insert group received Mydriasert® containing phenylephrine and tropicamide. The mydriasis was evaluated 75 minutes after the introduction of the mydriatic agents. Results The mydriasis was successfully achieved in both eyes in 97.5% of infants in the insert group and 90% in the eye drop group at 75 minutes after dispensation. The efficacy of the insert was non-inferior compared to the eye drops. To reach effective mydriasis, the insert group required fewer nursing interventions for one patient comparing to the eye drop group. Good general and local tolerance was observed in the two groups. However two patients reported an adverse event as bradycardia and gastro-oesophageal reflux that could be related to neonate pathology. Conclusions Mydriasis obtained with the ophthalmic insert Mydriasert® was not inferior compared to standard eye drop treatment. Insert reduced the number of nursing interventions to obtain mydriasis for a fundus examination. [ABSTRACT FROM AUTHOR]

Summary: Fluconazole is a triazole antifungal agent that is widely used in the nursery. It is available in both intravenous and oral formulation, and is active against most of the fungal pathogens that require treatment when retrieved from culture samples in neonatal intensive care units. Although clinical use has been wide for over 15 years, there have been small safety and efficacy studies completed in young infants. Randomised clinical trials assessing effectiveness of this agent in prevention of systemic fungal infections in neonates have been published in the last decade, and one large additional randomised study has been recently completed. Nevertheless, a certain degree of uncertainty still exists regarding the kinetics and appropriate dosing of this agent in premature and term infants, as well as regarding safety. Areas of poignant debate include the feasibility of loading dose strategies, appropriate dosages in the early days of life in the different subgroups of preterm infants, and long-term safety of fluconazole administered in prophylaxis during the first weeks of life in extremely premature infants. This paper reviews the most recent evidence on fluconazole and its role in the NICU settings. [ABSTRACT FROM AUTHOR]

Some patients with chronic hepatitis C develop liver/kidney microsome type 1 antibodies. Some of these autoantibodies are directed against the cytochrome P450IID6. The aim of this study was to characterize the immunogenic sites on the P450IID6 molecule recognized by autoantibodies from individuals infected with the hepatitis C virus. Serum from 24 patients with markers of hepatitis C infection and liver/kidney microsome type 1 antibodies were tested by immunoblotting with human liver microsomal proteins. Eight of them with anti-P450IID6 antibodies were tested with synthetic peptides representing P450IID6 putative immunogenic sites and for their capacity to inhibit in vitro P450IID6 enzymatic activity. Anti-P450IID6 antibodies in the sera of chronic hepatitis C patients were of IgG subclass 1 and in one patient also of IgM type. These sera recognized different P450IID6 peptide sequences consisting of amino acids (aa) 200-214 and aa 271-339. The synthetic peptide between aa 321 and 339 appears to represent the main antigenic site. Five out of eight anti-P450IID6 positive sera were also able to inhibit P450IID6 enzymatic activity in vitro at a dilution of 1:100. The anti-P450IID6 autoimmune response in chronic hepatitis C patients is polyclonal, probably inducible, and maintained by the liberation of P450IID6 by hepatocyte lysis. The characterization of the P450IID6 immunogenic site recognized by patients with hepatitis C infection may enable a specific test to be designed to identify those patients with autoimmune hepatitis type 2. [ABSTRACT FROM AUTHOR]

Background: Pharmacokinetics data on ceftazidime are sparse for the paediatric population, particularly for children with cystic fibrosis (CF) or severe infections.Objectives: To characterize the population pharmacokinetics of ceftazidime in critically ill children, identify covariates that affect drug disposition and evaluate the current dosing regimens.Methods: The study was registered with Clinicaltrials.gov (NCT01344512). Children receiving ceftazidime were selected in 13 French hospitals. Plasma concentrations were determined by UPLC-MS/MS. Population pharmacokinetic analyses were performed using NONMEN software.Results: One hundred and eight patients, aged 28 days to 12 years, with CF (n = 32), haematology and/or oncology disorders (n = 47) or severe infection (n = 29) were included. Ceftazidime was administered by continuous or intermittent infusions; 271 samples were available for analysis. A two-compartment model with first-order elimination and allometric scaling was developed and covariate analysis showed that ceftazidime pharmacokinetics were also significantly affected by CLCR and CF. Ceftazidime clearance was 82% higher in CF than in non-CF patients. Monte Carlo simulations showed that the percentage of target attainment (PTA) for the target of T>MIC = 65% was (i) lower in CF than in non-CF children with intermittent infusions and (ii) higher with continuous than intermittent infusion in all children.Conclusions: The population pharmacokinetics model for ceftazidime in children was influenced by body weight, CLCR and CF. A higher PTA was obtained with continuous versus intermittent infusions. Further studies should explore the benefits of continuous versus intermittent infusion of ceftazidime, including current versus increased doses in CF children. [ABSTRACT FROM AUTHOR]

Objectives: To determine the ciprofloxacin population pharmacokinetics in paediatric patients and the impact of underlying disease and evaluate the appropriateness of current dosage regimens.Patients and methods: Plasma concentrations of ciprofloxacin from children treated with ciprofloxacin were measured by HPLC. The pharmacokinetic population analysis was performed using NONMEM v7.2 (Icon Development Solutions, USA).Results: Two datasets were combined and 128 plasma concentrations in 60 patients aged 5.6 years (range 0.3-18.9), treated with a median daily dose of 30.0 mg/kg (range 6.5-52.0) presenting with sickle cell disease (SCD; n = 20, 33%), haemopathy (n = 15, 25%), cystic fibrosis (CF; n = 3, 5%) and other diseases (n  =  22, 37%) were analysed. Data were best described by a two-compartment model with first-order elimination. Ciprofloxacin clearance (mean ±  SD) was 0.81 ± 0.30 L/h/kg, increased allometrically with weight, decreased with increasing creatinine concentration, was 89% higher in SCD compared with non-SCD patients and increased by 0.95 L/h/kg per year of age. The volume of distribution was 6.9 L/kg and depended only on the weight. Monte Carlo simulations were performed separately in SCD and non-SCD patients to target an AUC/MIC ratio >125 at steady-state, required for antibacterial efficacy, and recommendations of dosing regimens were proposed.Conclusions: In addition to known covariates, ciprofloxacin clearance is greater in SCD children compared with non-SCD patients. The dosing of this agent needs to be adapted to this subgroup of patients. [ABSTRACT FROM AUTHOR]

What is known The neonatal intensive care units ( NICUs) are at the highest risk of drug dose error of all hospital wards. NICUs also have the most complicated prescription modalities. The computerization of the prescription process is currently recommended to decrease the risk of preventable adverse drug effects ( pADEs) in NICUs. However, Computer Prescribing Order Entry-Clinical Decision Support (C.P.O.E./C.D.S.) systems have been poorly studied in NICUs, and their technical compatibility with neonatal specificities has been limited. Objectives We set up a performance study of the preselected prescription of drugs for neonates, which limited the role of the prescriber to choosing the drugs and their indications. Methods A single 29 bed neonatal ward used this neonatal C.P.O.E./C.D.S. system for all prescriptions of all hospitalized newborns over an 18-month period. The preselected prescription of drugs was based on the indication, gestational age, body weight and post-natal age. The therapeutic protocols were provided by a formulary reference (330 drugs) that had been specifically designed for newborns. The preselected prescription also gave complete information about preparation and administration of drugs by nurses. The prescriber was allowed to modify the preselected prescription but alarms provided warning when the prescription was outside the recommended range. The main clinical characteristics and all items of each line of prescription were stored in a data warehouse, thus enabling this study to take place. Results Seven hundred and sixty successive newborns (from 24 to 42 weeks' gestation) were prescribed 52 392 lines of prescription corresponding to 65 drugs; About 30·4% of neonates had at least one out of licensed prescription; A prescription out of the recommended range for daily dose was recorded for 1·0% of all drug prescriptions. What is new? The C.P.O.E./C.D.S. systems can currently provide a complete preselected prescription in NICUs according to dose rules, which are specific to newborns and also comply with local specificities (therapeutic protocols and formulation of drugs). The role of the prescriber is limited to the choice of drugs and their indications. The prescriber still retains the possibility of modifying each item of the prescription, with all other prescription items being calculated by the C.P.O.E. system. In these conditions, the prescribers rarely modified the preselected prescription and the rate of out of range prescription was low. A multicentric study is required to confirm and extend these observations. Conclusions This study showed the feasibility of preselected prescription in NICUs and a low rate of out of range prescriptions. The preselected prescription could play a key role in lowering the dose error rate in NICUs. [ABSTRACT FROM AUTHOR]

Résumé La prescription néonatale des antibiotiques pose le problème d’une grande variabilité de pratiques tant au niveau national qu’international. Ceci reflète un manque d’évaluation de cette classe thérapeutique, pourtant largement utilisée. Face à ce constat, un travail d’optimisation de la prescription s’impose pour assurer chez le nouveau-né l’efficacité et la sécurité du traitement et pour diminuer les risques d’acquisition de résistances microbiennes. La prescription doit être sous-tendue par la connaissance des données de pharmacocinétique/pharmacodynamie du développement. Les études rigoureuses, conduites en collaboration entre néonatologues et pharmacologues pédiatres, sont indispensables pour disposer de schémas posologiques validés en néonatologie. Summary There is wide variation in neonatal dosages of antibiotics in clinical practice, both nationally and internationally. This reflects the lack of evaluation of drugs in this therapeutic class, although widely prescribed. Given this situation, optimization of antibiotic prescription is required to ensure efficacy and safety of neonatal treatment and reduce microbial resistance. Rational prescription should be based on the knowledge of developmental pharmacokinetics and pharmacodynamics. Rigorous studies, conducted in collaboration between neonatologists and pharmacologists, are essential to develop and validate evidence-based neonatal dosage regimens. [ABSTRACT FROM AUTHOR]

Objectives: CoNS are the most common cause of neonatal late-onset sepsis. Information on the vancomycin pharmacokinetics/pharmacodynamics against CoNS is limited. The aim of this study was to characterize vancomycin pharmacokinetic/pharmacodynamic relationships for CoNS and investigate neonatal optimal dosage regimens.Methods: A hollow fibre and a novel rabbit model of neonatal central line-associated bloodstream CoNS infections were developed. The results were then bridged to neonates by use of population pharmacokinetic techniques and Monte Carlo simulations.Results: There was a dose-dependent reduction in the total bacterial population and C-reactive protein levels. The AUC/MIC and Cmax/MIC ratios were strongly linked with total and mutant resistant cell kill. Maximal amplification of resistance was observed in vitro at an fAUC/MIC of 200 mg · h/L. Simulations predicted that neonates <29 weeks post-menstrual age are underdosed with standard regimens with respect to older age groups.Conclusions: The AUC/MIC and Cmax/MIC ratios are the pharmacodynamic indices that best explain total and resistant cell kill in CoNS infection. This suggests that less-fractionated regimens are appropriate for clinical use and continuous infusions may be associated with increased risk of emergence of antimicrobial resistance. This study has provided the pharmacodynamic evidence to inform an optimized neonatal dosage regimen to take into a randomized controlled trial. [ABSTRACT FROM AUTHOR]

Résumé Des textes éthiques et réglementaires encadrent le consentement en recherche clinique. Cependant leur application est parfois complexe en raison de difficultés propres à la pédiatrie. Sans pour autant s’écarter de leur respect strict, l’investigateur a ici un rôle central et doit en la matière s’impliquer au regard du respect des bonnes pratiques, de celui de la loi et des principes éthiques justifiant l’expérimentation humaine. Nous avons souhaité donner un éclairage qui permette de ne pas se laisser déborder par des exigences contraires à la législation française ou à l’éthique et plus en relation avec la protection du sponsor de la recherche qu’avec celle du patient, en particulier dans le cadre des essais pédiatriques. Summary Ethical and regulatory documents frame informed consent in pediatric research; their application is obligatory but may be complex. In this specific context, pediatric investigators have a central ethical role to play to ensure the strict respect of regulatory and ethical requirements adapted to the French legal, social, and cultural context as well as good clinical practices. This article attempts to shed light on the considerations that can allow researchers to come to terms with industrial and institutional demands while responding to the needs of patients, particularly in the domain of pediatric research. [ABSTRACT FROM AUTHOR]

Résumé Les recherches en pédiatrie portent sur l’enfant qui, juridiquement, n’a pas atteint l’âge de la majorité civile et est donc placé sous un régime de protection. La présentation de la recherche à ses représentants légaux permet d’obtenir leur consentement qui doit s’accompagner de l’assentiment de l’enfant. L’objectif de ce travail est de rappeler les évènements et textes importants expliquant les dispositions actuelles. Pour cela, les dispositions juridiques encadrant la démarche d’obtention du consentement sont revues et discutées dans cet article. Il est important de rappeler qu’il est de la responsabilité de l’investigateur de respecter ces obligations réglementaires mais que son implication éthique doit permettre un consentement libre et éclairé à la recherche dans des conditions souvent difficiles propres à la pédiatrie. Summary In pediatric research, the patient is legally a minor and therefore protected by law. Research can only be conducted after parental consent and patient assent have been obtained. In this context, this review discusses the historical events and documents related to all ethical precautions and obligations. It also underlines that physicians shall respect all legal measures, but that individual involvement must comply with ethical standards while taking into account issues particular to pediatric research related to parental consent and child assent to clinical trials. [ABSTRACT FROM AUTHOR]

Unlabelled: The European Paediatric Regulation mandated the European Commission to fund research on off-patent medicines with demonstrated therapeutic interest for children. Responding to this mandate, five FP7 project calls were launched and 20 projects were granted. This paper aims to detail the funded projects and their preliminary results. Publicly available sources have been consulted and a descriptive analysis has been performed. Twenty Research Consortia including 246 partners in 29 European and non-European countries were created (involving 129 universities or public-funded research organisations, 51 private companies with 40 SMEs, 7 patient associations). The funded projects investigate 24 medicines, covering 10 therapeutic areas in all paediatric age groups. In response to the Paediatric Regulation and to apply for a Paediatric Use Marketing Authorisation, 15 Paediatric Investigation Plans have been granted by the EMA-Paediatric Committee, including 71 studies of whom 29 paediatric clinical trials, leading to a total of 7,300 children to be recruited in more than 380 investigational centres.Conclusion: Notwithstanding the EU contribution for each study is lower than similar publicly funded projects, and also considering the complexity of paediatric research, these projects are performing high-quality research and are progressing towards the increase of new paediatric medicines on the market. Private-public partnerships have been effectively implemented, providing a good example for future collaborative actions. Since these projects cover a limited number of off-patent drugs and many unmet therapeutic needs in paediatrics remain, it is crucial foreseeing new similar initiatives in forthcoming European funding programmes. [ABSTRACT FROM AUTHOR]

The European Paediatric Regulation mandated the European Commission to fund research on off-patent medicines with demonstrated therapeutic interest for children. Responding to this mandate, five FP7 project calls were launched and 20 projects were granted. This paper aims to detail the funded projects and their preliminary results. Publicly available sources have been consulted and a descriptive analysis has been performed. Twenty Research Consortia including 246 partners in 29 European and non-European countries were created (involving 129 universities or public-funded research organisations, 51 private companies with 40 SMEs, 7 patient associations). The funded projects investigate 24 medicines, covering 10 therapeutic areas in all paediatric age groups. In response to the Paediatric Regulation and to apply for a Paediatric Use Marketing Authorisation, 15 Paediatric Investigation Plans have been granted by the EMA-Paediatric Committee, including 71 studies of whom 29 paediatric clinical trials, leading to a total of 7,300 children to be recruited in more than 380 investigational centres. Conclusion: Notwithstanding the EU contribution for each study is lower than similar publicly funded projects, and also considering the complexity of paediatric research, these projects are performing high-quality research and are progressing towards the increase of new paediatric medicines on the market. Private-public partnerships have been effectively implemented, providing a good example for future collaborative actions. Since these projects cover a limited number of off-patent drugs and many unmet therapeutic needs in paediatrics remain, it is crucial foreseeing new similar initiatives in forthcoming European funding programmes. [ABSTRACT FROM AUTHOR]

Summary: Invasive Candida infections (ICI) have a high burden of morbidity and mortality in the neonatal setting. Although the identification of effective prophylactic strategies has recently led to the prevention of many episodes of systemic fungal disease, the identification of effective treatment strategies is still a priority. The correct choice of the most appropriate antifungal drug for treatment of such infections requires specific expertise, as well as careful consideration of a number of variables related both to the characteristics of the patient and to the peculiarities of these infections in neonates. The ideal antifungal drug for preterm neonates should have a good ability to target fungal biofilms, in order to prevent or improve the course of end-organ localisations. It should also be active against fluconazole-resistant species, as well as safe enough to be used with no or limited interference with other neonatal drugs. In this view, the echinocandin class of antifungal agents has recently proven to be a suitable option for treatment. However, further studies are warranted to better establish kinetics and appropriate dosing of these agents in premature and term infants, as well as their ability to improve late outcomes of ICI. [ABSTRACT FROM AUTHOR]

Summary: Candida infections are a major cause of morbidity and mortality in neonatal intensive care units. Mortality following Candida bloodstream infections is as high as 40%, and neurodevelopmental impairment is common among survivors. Because invasive fungal infections are common and extremely difficult to diagnose, empirical treatment with antifungal therapy should be considered in high-risk, low-birth-weight infants who fail to quickly respond to empirical antibacterial treatment. Risk factors to consider when deciding to administer empirical antifungal therapy include: prior exposure to third-generation cephalosporins, extreme prematurity, and presence of central venous catheters. [ABSTRACT FROM AUTHOR]

Introduction: la transplantation rénale est la technique de choix pour le traitement de l’insuffisance rénale chronique terminale chez l’enfant en permettant une croissance staturopondérale correcte et une meilleure qualité de vie. Matériel et méthode: 191 enfants d’âge moyen 10.8 ± 4.7 ans [1.5 ; 20.6] ont été greffés dans notre service entre 1989 et 2007, 167 pour la première fois (145 donneurs cadavériques, 22 donneurs vivants), 16 ont été greffés 2 fois et 8 ont eu une transplantation foie-rein. Les complications chirurgicales ont été analysées rétrospectivement. Résultats: La survie globale est de 93.1 %, la survie du greffon à 5 ans de 84 %. 42 (20.2 %) enfants ont eu une complication urologique : 3 (1.5 %) nécroses urétérales, 14 (6.4 %) sténoses urétérales ayant nécessité 6 reprises chirurgicales, 4 (2 %) lâchages d’anastomose et 21 (10.4 %) reflux vésico-urétéraux ayant conduit dans 2 cas à une injection endoscopique de macroplastique. L’utilisation d’une endoprothèse semblait diminuer le taux de complications post-opératoires : diminution par 2 du risque de sténose et par 3 du risque de lâchage anastomotique. 46 (23.1 %) enfants ont eu une complication vasculaire : 4 (2 %) thromboses artérielles ayant toutes conduit à la perte du greffon, 16 (7.9 %) sténoses artérielles, 3 (1.5 %) thromboses veineuses, 1 (0.5 %) saignement sur Maladie de Willebrandt ayant nécessité une transplantectomie d’hémostase. L’âge du donneur inférieur à 6 ans était un facteur favorisant de thrombose veineuse (7.4 % versus 0.7 %), artérielle (3.7 % versus 1.4 %) et sténose artérielle (25.9 % versus 5 %). Conclusion: Une meilleure sélection des greffons et l’utilisation systématique d’une endoprothèse permettraient une amélioration des résultats de transplantation rénale pédiatrique. [Copyright &y& Elsevier]

BACKGROUND: Pregnant women and infants who get influenza are at increased risk for severe illness. OBJECTIVE: To evaluate the immunogenicity and transplacental antibody transfer of 2009 pandemic influenza A(H1N1) vaccine administered during pregnancy. DESIGN: Prospective, multicenter, single-group clinical trial. (ClinicalTrials.gov registration number: NCT01024400) SETTING: Five level-3 perinatal centers in France. PATIENTS: 107 pregnant women between 22(0/7) and 32(0/7) weeks of gestation. INTERVENTION: An intramuscular dose of a nonadjuvanted H1N1 vaccine that contained 15 mcg of hemagglutinin. MEASUREMENTS: Proportion of women with an influenza antibody titer of 1:40 or greater at days 21 and 42 after vaccination, delivery, and 3 months after delivery. Seroconversion rate, fold increase in the geometric mean titer 21 days after vaccination, and proportion of neonates with an antibody titer of 1:40 or greater at birth were also assessed. RESULTS: At baseline, 19% of the women had an antibody titer of 1:40 or greater. At day 21, 98% of the women had an antibody titer of 1:40 or greater, the seroconversion rate was 93%, and the fold increase in geometric mean titer was 67.4. At day 42, delivery, and 3 months after delivery, 98%, 92%, and 90% of the women, respectively, had an antibody titer of 1:40 or greater. Ninety-five percent of the cord serum samples obtained from 88 neonates showed an antibody titer of 1:40 or greater. The median neonate-mother antibody titer ratio was 1.4. LIMITATIONS: Only healthy pregnant women were selected. Data on hemagglutination inhibition antibody titers of infants were reported only at birth. CONCLUSION: A single dose of a nonadjuvanted influenza A(H1N1) vaccine with 15 mcg of hemagglutinin triggered a strong immune response in pregnant women and a high rate of neonatal seroprotection. PRIMARY FUNDING SOURCE: French National Institute of Health and Medical Research. [ABSTRACT FROM AUTHOR]

Low-dose methotrexate (MTX) therapy is the cornerstone treatment of acute lymphoblastic leukemia (ALL) and may enhance the activation of 6-mercaptopurine (6-MP) to 6-thioguanine nucleotides (6-TGN). Yet, data have established that high-dose MTX (HDMTX) hampers the accumulation of 6-TGN in red blood cells (RBC) and lymphoblasts. To clarify the pharmacokinetic interactions between these two antimetabolites, we serially measured RBC 6-TGN and MTX polyglutamates (MTXPG) levels following repeated courses of HDMTX (5 g/m² over 24 h) with daily oral 6-MP (25 mg/m²) during interval therapy in 20 children with ALL. HDMTX produced a rapid reduction in RBC 6-TGN 24 h after the start of MTX, and this effect was sustained at least by the third day (median decrease −21%; P < 0.001). However, a return to pre-infusion of 6-TGN levels was observed by the time of the following HDMTX course 14 days later ( P < 0.001). RBC MTX polyglutamates accumulation followed Michaelis–Menten kinetics but was not associated with the change in pre-infusion 6-TGN levels which remained stable during the interval period. HDMTX does not appear to enhance 6-MP activation to 6-TGN. Moreover, given that the deleterious effect of HDMTX on intracellular 6-MP disposition has been shown to be several folds greater in lymphoblasts than in RBC. Our data warrant additional studies elucidating the optimal MTX dose synergizing with 6-MP. [ABSTRACT FROM AUTHOR]

Irtan S, Maisin A, Baudouin V, Nivoche Y, Azoulay R, Jacqz-Aigrain E, El Ghoneimi A, Aigrain Y. Renal transplantation in children: Critical analysis of age related surgical complications. Pediatr Transplantation 2010: 14:512–519. © 2010 John Wiley & Sons A/S. To determine age-related risk factors of urological and vascular complications. We performed a retrospective analysis of the data of 202 renal transplantations in 193 children between 1989 and 2007 at a single institution. Out of 193 grafts (combined renal and liver grafts were excluded), we observed urological complications in 42 cases (21.7%) leading to graft loss in one case and vascular complications in 27 cases (13.9%) leading to graft loss in seven. The urological complications were VUR (n = 25, 12.4%), ureteral stricture (n = 10, 5%), anastomotic leak (n = 4, 2%), ureteral necrosis (n = 2, 1%), and incrustative pyelitis (n = 1, 0.5%). Vascular complications were arterial stricture (n = 14, 7.2%), arterial thrombosis (n = 4, 2%), venous thrombosis (n = 2, 1%), and others (n = 7). Donors aged less than six yr were a risk factor of vascular complications leading to graft loss (p = 0.0001), whereas patients with PUV had more urological complications (p = 0.001). Overall patient and graft survival is 93.1% and 84% at five yr, respectively. Surgical complications remain a major cause of graft loss (12%) and morbidity in children’s kidney transplantation (38.9%). Young age of donors is the major risk factor of early graft loss as a result of vascular complication. However, donor selection based on age is limited by the shortage of organs. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to analyze retrospectively and critically the different steps of the individual dose adjustment procedure employed in the concentration-controlled (CC) versus fixed-dose trial Apomygre, which showed that mycophenolate mofetil (MMF) dose adjustment using a limited sampling strategy significantly reduced the risk of treatment failures and acute rejection in renal transplants at one year posttransplantation. The number of AUCs performed during the study and circumstances of collection, time of blood sampling, Bayesian mycophenolic acid (MPA) area-under-the-curve (AUC) estimation procedures and physicians’ compliance with MMF dose recommendations were retrospectively analyzed. 92% of AUCs scheduled over the study were actually performed. Sampling times were very well respected. Bayesian estimation of MPA exposure was done by the pharmacologists locally in accordance with the protocol instructions and the AUC estimates obtained were virtually all confirmed a posteriori. On the other hand, a second AUC estimated by multiple linear regression could only be provided for 84% of the profiles and showed a large overestimation with respect to Bayesian estimates for AUC values between 10 and 55mgh/L. In the CC arm, a very good physicians’ compliance was observed (85%) and application of the dose recommendations led to higher values of AUCs (42.1±14.6mgh/L versus 36.7±16.3mgh/L, p =0.0035) and to more AUCs in the target range (69% versus 56%, p =0.0343) than when dose recommendations were not applied. By analyzing in detail the feasibility criteria of MMF Bayesian dose adjustment, this study highlighted the requirements for successful extrapolation of the Apomygre trial results to routine practice: (i) respect of the PK sampling time-windows; (ii) use of relevant tools for accurate drug exposure estimation and dose adjustment calculation; and (iii) good compliance of the physicians with regard to the recommended doses. [Copyright &y& Elsevier]

Purpose: To test bioequivalence of oral vitamin E formulations, water-soluble tocofersolan (test) and water-miscible (reference), in healthy adult volunteers, and their bioavailability in children with chronic cholestasis or cystic fibrosis. Methods: In a two-way open randomized single dose cross-over design, 1200 IU were administered in 12 healthy volunteers and 100 IU/kg in 12 children with chronic cholestasis or cystic fibrosis. Results: In healthy volunteers, formulations were not bioequivalent with a higher exposure to tocofersolan. In cholestatic children tocofersolan bioavailability was significantly higher than reference formulation (maximum plasma concentration: P = 0·008 and AUC: P = 0·0026). Bioavailability was not statistically different in cystic fibrosis. Conclusions: Oral tocofersolan was more bioavailable than the reference formulation in children with chronic cholestasis and similarly bioavailable in cystic fibrosis. Tocofersolan may represent an alternative to painful intramuscular vitamin E injections in chronic cholestasis, or to other oral formulations in cystic fibrosis. [ABSTRACT FROM AUTHOR]

Abstract: A sensitive method of determination of ketamine and norketamine by micro-liquid chromatography/mass spectrometry was developed as part of a clinical trial in a pediatric population. Compounds were extracted from 100μl plasma samples using solid-phase extraction on Oasis® MCX cartridges. Separation was achieved on a C18 micro-column with a mobile phase composed of formic acid 0.1% and acetonitrile (90/10, v/v). Detection of ketamine, norketamine and their internal standard norketamine D4 was performed using selected ion monitoring at m/z 238.2, 224.2 and 228.2, respectively. Under these conditions, no loss of signal due to matrix effect was found and time of analysis did not exceed 10min. Extracted calibration curves were linear from 5 to 500ng/ml for each analyte, with correlation coefficients over 0.999. Intra- and inter-day validation studies showed mean recoveries between 98.1 and 101.7% and a relative standard deviation below 1.9%. Extraction recoveries ranged from 84.8 to 89.8% for both ketamine and norketamine. Limit of quantification was 4ng/ml for each analyte. [Copyright &y& Elsevier]

Background and objective:  The activity of thiopurine S-methyltransferase (TPMT), a key enzyme in the metabolism of purine analogues, displays wide inter-subject variability partly due to a genetic polymorphism. Previous studies have suggested adjusting purine analogues dosing according to TPMT activity but measurements are costly and time-consuming. It is still unclear, especially under treatment, whether the simpler TPMT genotyping reliably predicts enzyme activity. Our aim was to study the possible correlation of TPMT genotype with phenotype. Methods:  We determined the genotypic status and TMPT activity, at diagnosis and after 6 months of maintenance therapy, of 118 children with acute lymphoblastic leukaemia (ALL). Results and Discussion:  Eighty-nine per cent of the children had a homozygous wild-type genotype (group 1), 11% had one or two mutant allele(s) (group 2). At both time points, TPMT activity (U/mL peripheral red blood cell) was significantly higher in group 1 than in group 2 ( P < 0·001) but inter-group levels overlapped considerably. There was considerable heterogeneity in the percentage increase in TPMT activity after therapy, and little correlation between metabolites ratio [6-methylmercaptopurine derivative/6-thioguanine nucleotides (6-TGN)] and TPMT activity at the end of 6 months’ maintenance treatment. These results show that TPMT activity cannot be used as an accurate tool for 6-mercaptopurine monitoring. Conclusion:  Genotyping at diagnosis identifies patients with a homozygous mutant TPMT and may prevent severe and life-threatening toxicity. ALL treatment monitoring should preferentially be based on repeated determinations of intracellular active metabolites (6-TGN) and methylated metabolites. [ABSTRACT FROM AUTHOR]

Background. – Fetal alcohol syndrome (FAS) is a major problem in the Reunion Island and the Public Health Authorities decided to determine its prevalence in their medico-social centers on 31 December 1996.Material and methods. – A questionnaire was etablished to identify affected patients in the 20 medico-social centers in charge of 1320 children. Eighty-eight children were selected and 87 could be analyzed.Results. – Sixty-four of 87 (76.3%) were FAS and 23 of 87 (23.7%) had closely alcohol-related diseases. The prevalence was between 7.1 and 14.1% and lower than expected from available data.Conclusion. – The study allowed to precise the social and familial factors predisposing to alcohol addiction during pregnancy. A TV prevention message will be broadcasted after this study. [ABSTRACT FROM AUTHOR]

6-Mercaptopurine (6-MP) is metabolized by thiopurine S-methyltransferase (TPMT), an enzyme subject to genetic polymorphism. We investigated the relationships between the TPMT locus (TPMT activity and genotype) and the pharmacological response to 6-MP during maintenance therapy of 78 children with acute lymphoblastic leukemia (ALL). For each patient, 6-MP dosage, leukocyte counts and occurrence of infectious episodes were monitored on an 8 week basis. Higher 6-MP dosage was associated with higher TPMT activity (P = 0.03) and higher average leukocyte counts (P < 0.01). Eight patients (10%) carrying a TPMT mutant genotype (one homozygous and seven heterozygous) received lower 6-MP doses (average: 48 vs 65 mg/m2/day; P = 0.02) and had on average lower leukocyte counts (2834 vs 3398 cells/mm3; P = 0.003) than patients carrying the wild-type TPMT genotype. Higher occurrence of infectious episodes graded 2 or 3 was correlated with higher 6-MP dosage (P < 0.01) but no difference was observed between TPMT mutants and TPMT wild-type patients. Patients who received 6-MP dosage above the group median (62 mg/m2/day) or having a TPMT activity above the group median (21.5 nmol/h/ml) had a higher percentage of 8 week periods with infectious episodes requiring treatment (34% vs 17% and 33% vs 19%, respectively) than those with 6-MP dose or TPMT activity below the group median (P < 0.01). In the last 25 patients enrolled in the study, steady-state erythrocyte thioguanine nucleotide (TGN) concentrations were associated with lower leukocyte counts (P= 0.01) but not with a higher occurrence of infectious episodes. In contrast, higher steady-state erythrocyte methylmercaptopurine nucleotide (MeMPN) concentrations were associated with higher 6-MP dosage (P< 0.01) and higher occurrence of infectious episodes (P < 0.001). In conclusion, during maintenance therapy of ALL, children with higher TPMT activity receive a higher 6-MP dosage and may have infectious episodes caused by metabolism of 6-MP into methylmercaptopurine nucleotides. [ABSTRACT FROM AUTHOR]

Background: Data on the proton pump inhibitor lansoprazole in paediatric patients are limited. Aim: To investigate the pharmacokinetics, optimal dosage and efficacy of lansoprazole in paediatric patients. Methods: A 24-h gastric pH recording and a pharmacokinetic study were performed after 7 days of lansoprazole, 17 mg/m2, in 23 patients with reflux oesophagitis (median age, 3.5 years). Response was defined as pH > 3 for > 65% of the recording. The dosage was doubled in non-responders. Patients with no response on day 14 were excluded. Responders underwent endoscopy after 4 weeks on the response-inducing dosage; abnormal findings led to a repeat endoscopy after four additional weeks. Results: Nine patients responded to 17 mg/m2 and six to 30.3 mg/m2. On day 7, time with pH > 3 was significantly correlated with the area under the plasma concentration–time curve (P=0.003). The area under the plasma concentration–time curve was significantly greater in the nine responders to 17 mg/m2 than in the 14 other patients. Pharmacokinetic parameters were similar in responders and non-responders to the higher dose. After 4 weeks, oesophagitis was healed in 80% of responders. Adverse events occurred in three patients and required treatment discontinuation in one. Conclusions: Lansoprazole is effective and safe in children. The optimal starting dosage is 30 mg/m2 or 1.4 mg/kg. [ABSTRACT FROM AUTHOR]

Summary: Background: We sought to describe the incidence, pathogen distribution, and mortality associated with blood culture-proven sepsis in young infants with congenital heart disease (CHD) admitted to a neonatal intensive care unit (NICU). Methods: Cohort study of all blood cultures obtained from infants with CHD between 4 and 120 days of age cared for in 250 NICUs managed by the Pediatrix Medical Group in the United States between 1996 and 2007. Results: Of 11,638 infants with CHD, 656 (6%) had 821 episodes of sepsis: a cumulative incidence of 71/1000 admissions. Gram-positive organisms were the most common cause (64%), and coagulase-negative Staphylococcus and Staphylococcus aureus were the most frequently isolated species. On multivariable regression, infants with sepsis were more likely to die compared to infants with sterile blood cultures (odds ratio [OR] = 1.53 [95% confidence interval: 1.09, 2.13]). Infants with Gram-negative bacteraemia and candidaemia were more likely to die than infants with sterile blood cultures (OR = 2.01 [1.20, 3.37], and OR = 3.18 [1.60, 6.34], respectively). Conclusion: Infants with CHD have a high incidence of culture-proven sepsis, especially with staphylococcal organisms. Gram-negative bacteraemia and candidaemia are strongly associated with increased mortality in this group of young infants. [ABSTRACT FROM AUTHOR]

Summary: Invasive disseminated neonatal aspergillosis is an uncommon disease, with only scattered reports in literature in the last few years. Here we report on a 25-week gestational age, 730 g at birth preterm female infant who developed on day-of-life 10 multiple cutaneous exhulcerative lesions in her right arm, trunk and abdomen. Early recognition and diagnosis of these lesions as a due to cutaneous initial symptom of cutaneous disseminated aspergillosis, as well as prompt treatment with Liposomal amphotericin B + Itraconazole, secured successful recovery from the systemic infection. Skin lesions healed without any surgical treatment. The infant was discharged in good health. Long-term follow-up at three years of age revealed normality of all neurodevelopmental and cognitive parameters. To our knowledge, this is one of the very few cases of survival, free from sequelae, for a preterm infant affected by neonatal cutaneous disseminated aspergillosis. [ABSTRACT FROM AUTHOR]