Dissertations / Theses on the topic 'Pediatric pharmacology'

Thesis (Ph.D. )--University of Tennessee Health Science Center, 2007.<br>Title from title page screen (viewed on June 19, 2008). Research advisor: Bernd Meibohm, Ph.D. Document formatted into pages (xiv, 100 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 96-100).

Background. Medication-related patient injuries (adverse drug events, ADEs) are an important problem in all hospitalised populations; however, the potential for injury is reported to be greater in children than adults. Many ADEs are due to error and therefore could be prevented. Data regarding the risk factors (or predictors) for these events in paediatric inpatients is limited. It was hypothesised that "identification of risk factors for ADEs and medication errors in the paediatric inpatient setting will inform likely prevention strategies". Aims. To determine the frequency, nature and risk factors for ADEs and potential ADEs occurring in a paediatric inpatient population; to assess the vulnerable processes in the neonatal intensive care unit (NICU) medication use process; and to provide recommendations for the targeting of likely prevention strategies. Setting. A general paediatric ward (PW), postnatal ward (PNW) and NICU of a University- affiliated urban general hospital. Design. There were two study components: the medEVENT study which involved identification of actual ADEs and potential ADEs over a twelve week period, through prospective review of medical records, medication charts and administration records along with voluntary and solicited staff report and parent interview; and the FMEA study which used a proactive risk assessment technique, Failure Mode and Effect Analysis (FMEA), to rank all potential failures in the NICU medication use process according to risk. Results. In the MedEVENT study 3160 prescription episodes were reviewed (which represented 520 admissions, 3037 patient-days) and revealed a total of 67 ADEs and 77 potential ADEs. The greatest number of events occurred in NICU with very few events in the PNW. However, paediatric surgical admissions experienced the highest rate of ADEs per 1000 patient-days (80) as compared to medical (65) then NICU admissions (19). Over half of the ADEs were deemed preventable, 38 (57%), with the �more serious� ADEs more likely to be preventable than �not serious� ADEs. The impact on hospital resources was considerable with the cost attributed to extra bed days due to ADEs to be $NZD 50,000. Dosing errors were the most common type of error, particularly when prescribing and administering medications. Antibacterial and narcotic analgesics were commonly implicated, as was the intravenous route of administration. Few events were related to unlicensed use of medications. For ADEs, the major risk factors when analysed by admission, were greater medication exposure and increasing age; by prescription, were increasing age, oral route and narcotics and antibacterial agents; for paediatric ward admission, were increasing age and increased length of stay; and for NICU admission, no major risk factors emerged. For potential ADEs, the major risk factors when analysed by admission were greater medication exposure; by prescription, were junior prescriber, intravenous route, narcotics and antibacterials; for paediatric ward admission, were junior prescriber and narcotics; and for NICU admission were antibacterials, electrolytes and umbilical venous catheter administration. Neither ADEs nor potential ADEs were associated with unlicensed use of medicines or high alert status drugs. The FMEA study identified 72 potential failures in the NICU medication use process with 193 associated causes and effects. Multiple failures were possible in the process of �prescribing medication� and in the process of �preparation of medication for administration�. The highest ranking issues were found to occur at the administration stage. Common potential failures related to errors in the dose, timing of administration, infusion pump settings and route of administration. Conclusions. Analysis of the risk factors of ADEs and potential ADEs found that the most vulnerable processes were when prescribing and when preparing a medicine for administration; especially when involving narcotic and antibacterial agents and for children with greater medication exposure Strategies that selectively target these high risk areas are therefore likely to have the greatest impact on preventing drug-related injuries in hospitalised children.

La cloroquina (CQ) sigue siendo el medicamento de primera línea en todo el mundo para el tratamiento de la malaria por Plasmodium vivax. La dosis recomendada por la OMS es de 25 mg/kg/peso, independientemente de la edad del paciente. Por otro lado, la farmacocinética y la farmacodinámica de los medicamentos; diferente en los niños en relación que los adultos, puede influir en la concentración del fármaco en la sangre y convertirse en factor de riesgo para el fracaso terapéutico y /o resistencia a CQ. Objetivo: Evaluar la eficacia terapéutica de la cloroquina en infecciones por Plasmodium vivax y la dosis pediátrica como factor de riesgo, asociado al fracaso terapéutico y/o resistencia. Métodos: A todos los pacientes que cumplieron con los criterios de inclusión y exclusión se les administro 25mg/kg de CQ por tres días, bajo estricta supervisión, los cuales fueron seguidos por 28 días. La concentración de CQ+desetilcloroquina (DCQ) en sangre ha sido determinada en los días 7 y 28 de seguimiento y/o en el día del fracaso terapéutico (FT), y solo al final del seguimiento se les administró primaquina. Modelos de regresión y correlación se utilizaron para evaluar y comparar la dosis CQ tomada por mg/kg/peso (dosis real), la dosis de CQ calculada en base al área de superficie corporal (ASC) (dosis teórica), con los niveles de CQ en la sangre en el día 7 y la edad en años de la población. Los contrastes de hipótesis se han evaluado con un riesgo alfa de 5% y las estimaciones con un intervalo de confianza del 95%. Resultados: Entre mayo y noviembre del 2011, cien pacientes fueron adheridos al estudio, dos se perdieron durante el seguimiento y otros dos fueron excluidos más tarde por violar el protocolo. De los 96 pacientes que completaron el seguimiento, 10 presentaron FT; uno de ellos presento parasitémia continua hasta el día 7, tres en el día 21, y seis en el día 28 del seguimiento. La media geométrica de CQ+DCQ el día 7 fue 321,7 ng/ml (rango 197-535 ng/ml).En seis pacientes con FT las concentraciones de CQ+DCQ en sangre en el día de FT ha sido >100 ng/ml. La tasa de resistencia fue del 6,5% en la población en general. La diferencia entre las dosis real y teórica fue de: -181.206 mg (IC95%: -195,39; -167,02 mg) en los 5-9 años de edad y -71,39 mg (IC95%:-118,61;-23,99 mg) en el 10-14 años de edad. La concentraciones de CQ en la sangre en el día 7 ha sido diferente en mayores y menores de 15 años (p= 0,008). Se ha encontrado una correlación negativa entre la dosis real y teórica y la edad (R2= 0,529, p= 0,001). También se encontró una correlación negativa entre la diferencia de estas dosis (mg) y concentraciones de CQ en el día 7 del seguimiento (ng/ml) (r= -0,337, p= 0,001). De la misma manera en los niños menores de 15 años la tasa de FT ha sido mayor que los adultos. (28% vs. 4,2%, respectivamente) (Kaplan-Meier p= 0,005). Conclusión: Se comprueba resistencia de la CQ en infecciones por P. vivax en la población general de la zona amazónica de Bolivia, la resistencia se encuentra más acentuada en jóvenes que en adultos, cuya edad media es <15 años. La dosis de cloroquina real es menor que la dosis teórica calculada por ASC en <15 años, mientras que no se encontró esta diferencia en adultos. Con la dosis de 25 mg/kg/peso los menores de 15 años no alcanzan los mismos niveles de cloroquina en sangre del día 7 del seguimiento, que los adultos. Por estos resultados decimos que existe una sub-dosificación de Cloroquina en <15 años la que podría ser uno de los factores de riesgo que esté influenciando en la tasa de fracaso terapéutico y/o resistencia encontrada en niños; estos resultados sugieren la necesidad de revisar las dosis pediátricas de CQ utilizadas actualmente.<br>Chloroquine (CQ) remains the world's first-line drug for the treatment of Plasmodium vivax malaria. The dose recommended by WHO: 25mg/kg/weight, regardless of the age of the patient. Methods: All patients received 25mg/kg/weight for three days, followed for 28 days. The concentration of CQ+ decytilcloroquine (DCQ) in blood was measured on days 7 and 28 of the follow-up and / or the day of therapeutic failure (FT). Regression and correlation models are used to evaluate and compare the CQ dose taken by mg /kg/ weight (actual dose), the CQ dose calculated based on the body surface area (ASC) (theoretical dose), with the levels of CQ in the blood on day 7 and age. Results: Between May and November 2011, 100 patients were adherent and 96 completed the study. The geometric mean of CQ+DCQ on day 7 was 321.7 ng/ml (range 197-535 ng/ml). In six patients with FT the concentrations of CQ+DCQ in blood on FT day were>100 ng/ml. The rate of resistance of 6.5% in the general population. The difference between the actual and theoretical doses was -181.206 mg (95% CI: -195.39; -167.02 mg) at 5-9 years of age and -71.39 mg (95% CI: -118.61; -23.99 mg) at 10 -14 years old. Blood concentrations of CQ at day 7 were different in older and younger than 15 years (p= 0.008). (R2= 0.529, p= 0.001). A negative correlation was found between the difference of these doses (mg) and concentrations of CQ on day 7 of follow-up (ng/ml) (r= -0.337, p= 0.001). Similarly, in children younger than 15 years the FT rate has been higher than adults. (28% versus 4.2%, respectively) (Kaplan-Meier p= 0.005). Conclusion: CQ resistance is confirmed in P. vivax infections in the general population of the Amazonian zone of Bolivia, also there is sub-dosage of Chloroquine in <15 years which could be one of the risk factors that is influencing the rate of therapeutic failure and/or resistance, found in children; These results suggest the need to review the pediatric doses of CQ currently used.

El trastorn per dèficit d’atenció amb hiperactivitat (TDAH) és un trastorn del neurodesenvolupament caracteritzat per símptomes d’inatenció i/o hiperactivitat/impulsivitat. Nombrosos estudis suggereixen un important component genètic en l’etiologia del TDAH, amb una heretabilitat estimada del 70-80%. Tanmateix, la majoria de variants genètiques identificades només expliquen una petita proporció de la variabilitat fenotípica observada i la seva associació, en general, no ha estat replicada consistentment. A més, s’han descrit diversos factors ambientals que tendeixen a incrementar el risc de presentar TDAH i que sovint contribueixen a agreujar-ne les manifestacions. Les discrepàncies en els resultats obtinguts, per tant, podrien ser degudes, entre d’altres, a la influència de variables ambientals, capaces de modular els efectes dels factors genètics a través d’interaccions gen × ambient. Pel que fa a l’abordatge terapèutic del TDAH, el principal tractament farmacològic consisteix en l’administració de psicoestimulants com el metilfenidat (MPH), un potent inhibidor de la recaptació de dopamina. No obstant això, aproximadament un 30% dels pacients no respon adequadament al fàrmac, fet que podria estar determinat, en part, per influències genètiques. La recerca farmacogenètica del MPH s’ha centrat de forma quasi exclusiva en gens suposadament relacionats amb el seu mecanisme d’acció, entre els quals destaquen el transportador de dopamina (SLC6A3) i el receptor dopaminèrgic D4 (DRD4), malgrat que els resultats aportats han estat predominantment negatius o discordants. La majoria d’investigacions, a més, han avaluat un únic o un nombre molt reduït de polimorfismes en base a la seva presumpta rellevància funcional, sense tenir en compte la possible interacció entre ells o amb influències ambientals. L’objectiu de la present tesi doctoral fou, per una banda, aprofundir en els processos etiològics implicats en el TDAH mitjançant un estudi d’associació amb vuit gens candidats (DRD4, SLC6A3, COMT, ADRA2A, CES1, CYP2D6, LPHN3 i OPRM1) en què s’avaluaren dotze polimorfismes potencialment funcionals en una mostra de sis-cents quatre pacients adults i sis-cents onze individus control. A continuació, s’investigà la influència d’experiències estressants durant la infantesa en la gravetat del trastorn, així com la possible interacció entre l’adversitat ambiental i les variants genètiques de risc identificades. Els resultats de l’esmentat estudi revelaren la contribució de DRD4 en la persistència del TDAH a l’edat adulta i proporcionaren evidències preliminars sobre el seu paper com a mediador de l’efecte que els esdeveniments vitals adversos exerceixen en la gravetat de la simptomatologia. Per altra banda, es proposà identificar marcadors genètics de la resposta i la tolerabilitat al MPH. Per a aquesta finalitat, s’empraren dues estratègies complementàries. En primer lloc, s’examinaren cinquanta-set polimorfismes distribuïts al llarg dels principals gens de la neurotransmissió dopaminèrgica (DRD1-5, SLC6A3, TH, COMT i DBH) en una mostra de cent set pacients pediàtrics amb TDAH. A més, s’explorà la influència de variables ambientals pre i perinatals en els efectes del tractament, així com la presència d’interaccions gen × gen i gen × ambient. Els resultats de la segona investigació suggeriren la implicació de DRD3, DBH, TH i l’exposició prenatal al tabac en l’eficàcia clínica del MPH. Concretament, s’observà un major risc de resistència al tractament en individus susceptibles genèticament i amb mares fumadores durant l’embaràs mentre que l’aparició d’efectes adversos s’associà a la variabilitat a DBH i DRD2. En segon lloc, s’analitzà l’associació amb la resposta al MPH a escala genòmica en cent setanta-tres infants amb el trastorn. Les dades obtingudes es combinaren amb evidències biològiques i bioinformàtiques, fet que posà de manifest la participació de gens relacionats amb el desenvolupament i funció del sistema nerviós, malalties neurològiques i psiquiàtriques, com el dèficit d’aprenentatge, o la conducta, com el comportament hiperactiu. En definitiva, els resultats que conformen la present tesi doctoral aporten informació innovadora i rellevant al camp de l’etiologia i la farmacogenètica del TDAH a través de la identificació de loci genètics implicats en el sistema dopaminèrgic i el neurodesenvolupament, i de factors ambientals com els esdeveniments vitals estressants o el consum matern de tabac durant l’embaràs.<br>Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a strong genetic component. However, most of the identified genetic variants explain only a small proportion of the phenotypic variance. Additionally, several environmental factors have been reported to increase the risk and severity of ADHD. Thus, the absence of clear conclusions might be caused by environmental influences that moderate the effects of genetic factors through gene-environment interactions. Stimulant medications such as methylphenidate (MPH), a dopamine reuptake inhibitor, are generally the first-line choice in ADHD pharmacological treatment. Nevertheless, approximately 30% of ADHD patients do not respond favorably to treatment, which may reflect underlying genetic influences. Pharmacogenetic studies of MPH have focused on genes presumably related to its mechanism of action, especially the dopamine transporter (SLC6A3) and the dopamine receptor D4 (DRD4), although findings have been predominantly negative or inconsistent. Furthermore, the majority of investigations have evaluated a single or few polymorphisms based on their putative functional implications, without considering the possible interaction between them or with environmental factors. The objective of the present doctoral thesis was to elucidate the etiological processes implicated in ADHD through an association study with eight candidate genes (DRD4, SLC6A3, COMT, ADRA2A, CES1, CYP2D6, LPHN3 and OPRM1), which examined 12 potentially functional polymorphisms in a sample of 604 adult patients and 611 controls. We subsequently investigated the impact of childhood stressful experiences on the severity of ADHD, as well as the possible interaction between environmental adversity and the identified genetic risk variants. On the other hand, the doctoral thesis aimed to identify pharmacogenetic markers of MPH response and tolerability. Firstly, we analyzed 57 polymorphisms across the main genes of the dopaminergic neurotransmission (DRD1-5, SLC6A3, TH, COMT and DBH) in a sample of 107 ADHD pediatric patients. We also explored the influence of prenatal and perinatal risk factors on treatment effects, as well as the presence of gene-gene and gene-environment interactions. Secondly, we conducted a genome-wide association study of MPH response in 173 children with ADHD and we combined the data obtained with bioinformatic and biological evidence. The results of the present doctoral thesis provide innovative and relevant information to the field of ADHD etiology and pharmacogenetics through the identification of genetic loci implicated in the dopaminergic system and neurodevelopment, and environmental factors such as stressful life events or maternal smoking during pregnancy.

The purpose of this current study is to examine the impact of non-pharmacologic pain interventions administered by trained Child Life professionals in an emergency department on pain perception in children. Results showed no significant decrease in children's pain report during the medical procedure compared to before the medical procedure. However, pain after the medical procedure is significantly less than pain during the medical procedure.

Objectives: 1) To describe the state of the evidence for interventions in pediatric migraine, 2) to survey experts regarding non-inferiority margins in migraine research and 3) to design a clinical trial in this area of research. Methods: A systematic review was carried out to identify randomized, placebo-controlled trials of pharmaceutical and nutraceutical interventions used to prevent migraine in children and adolescents, using Cochrane methods. Secondly, neurologists with expertise in Headache Medicine were invited to participate in a survey regarding their opinions on non-inferiority margins for outcomes used in clinical trials of migraine interventions. Thirdly, a protocol was written for a three-arm, parallel-group, randomized trial comparing the efficacy and safety of topiramate, levetiracetam and placebo for the prophylaxis of pediatric migraine. Results: The systematic review identified 19 articles of 12 interventions for pediatric migraine. The quality of the evidence was poor and few conclusions could be made. Ninety-nine eligible respondents completed the survey and non-inferiority margins for six outcomes were determined. A randomized controlled trial protocol was developed to determine if topiramate and levetiracetam are superior to placebo, and if levetiracetam is non-inferior to topiramate for the prevention of migraines in children and adolescents. Conclusions: It is hoped that the results of this thesis can be applied to further the evidence in this area of clinical research.

La falta de disponibilidad de presentaciones comerciales adecuadas para la posología pediátrica todavía supone un gran problema, especialmente relevante en medicamentos con margen terapéutico estrecho, ya que puede derivar en infra o sobredosificaciones; o en niños que sufren enfermedades crónicas, condenados a tomar medicamentos mal adaptados y sufrir las consecuencias que ello supone; o en las ocasiones en las que se presentan casos de intolerancias o alergias hacia determinados excipientes. Todo ello obliga a realizar un gran número de fórmulas magistrales. Evidentemente, para solventar este problema, las formas farmacéuticas líquidas siguen siendo la mejor alternativa a las formas farmacéuticas sólidas, ya que ofrecen una serie de ventajas: . Versatilidad para el ajuste de dosis, frecuentemente modificada en estos pacientes en función del peso o de la respuesta clínica. . Facilidad de administración. . Fiabilidad de la dosificación. . Posibilidad de administración por sonda nasogástrica. Sin embargo, la variabilidad en el diseño de fórmulas magistrales, la falta de uniformidad en el caso de las suspensiones y el inconveniente de la menor estabilidad de las formas líquidas, conlleva la posibilidad de errores de medicación en el manejo de las dosificaciones. De aquí que la terapéutica en pacientes pediátricos o pacientes con dificultades para deglutir, dependa en gran medida de la elaboración de formulaciones magistrales adecuadas. Algunas de las patologías que requieren la realización de estos preparados para pacientes pediátricos incluyen la hipertensión pulmonar persistente del neonato, la insuficiencia cardiaca congestiva, el síndrome de abstinencia neonatal o las convulsiones. Por tanto, a la vista de lo anterior, en este trabajo se han desarrollado y estudiado un total de trece fórmulas magistrales líquidas de administración oral: dos fórmulas de sildenafilo, cuatro de espironolactona, dos de furosemida, tres de metadona y dos de fenobarbital. En el desarrollo de las fórmulas también se ha tenido en cuenta a la población diabética. Una vez establecida la fórmula cuali-cuantitativa de cada una de las formulaciones, se desarrolló y validó un método sensible y rápido como técnica analítica de referencia para la cuantificación de cada principio activo, para lo cual se determinó la linealidad, la precisión y la exactitud del método analítico; asimismo se determinaron los límites de cuantificación y detección para cada uno de los principios activos objeto de estudio. Los controles físico-químicos y microbiológicos que se llevaron a cabo con el fin de caracterizar las diferentes fórmulas fueron: 1. Características organolépticas (aspecto, color, olor). 2. Cuantificación del principio activo 3. Determinación del pH 4. Comportamiento reológico y viscosidad 5. Tamaño de partícula (sólo en el caso de las suspensiones) 6. Estabilidad óptica acelerada (sólo en el caso de las suspensiones). 7. Análisis microbiológico (Ph.Eur.) Para establecer su estabilidad, las formulaciones se almacenaron a tres temperaturas (4, 25 y 40 ºC) durante un periodo máximo de 90 días y se determinaron aquellos parámetros susceptibles de cambio a diferentes tiempos prefijados. Por otro lado, se realizaron controles biofarmacéuticos con el objeto de determinar la influencia de los excipientes en los procesos de liberación (estudios in vitro- ensayos de disolución) y absorción (estudio de la absorción a través de intestino delgado de cerdo) del principio activo. Los resultados obtenidos en esta Tesis Doctoral hacen posible una correcta conservación y dosificación de los principios activos estudiados (sildenafilo, espironolactona, furosemida, metadona y fenobarbital) cuando se formulan en formas líquidas de administración oral; garantizando la continuidad, la calidad y la eficacia de tratamientos pediátricos tales como la hipertensión pulmonar persistente del neonato, la insuficiencia cardiaca congestiva, el síndrome de abstinencia neonatal y las convulsiones neonatales, según corresponda.<br>The lack of availability of age appropriate dosage forms is still a big problem, especially relevant in drugs with narrow therapeutic index, as it can lead to under-or overdosing; children with cronical diseases; or in cases of allergies to certain excipients. This requires a large number of pharmaceutical compounding. To solve this problem, the liquid dosage forms remain the best alternative to the solid dosage forms because they offer advantages: • Versatility for dosage adjustment in these patients • Easy administration. • Reliability dosing. • Possibility of gavage. However, the variability in their design and the lower stability of the liquid forms, leads to the possibility of medication errors in handling dosages. Hence the therapy in pediatric patients or patients with swallowing difficulties, depend largely on the development of appropriate formulations. Therefore, in this work thirteen liquid pharmaceutical compounding for oral administration: two formulations of sildenafil, four of spironolactone, two of furosemide, three of methadone and two of Phenobarbital have been developed, taking into account also the diabetic population. An analytical method has been developed and validated using appropriates analytical techniques for the quantification of each active ingredient (API). Linearity, precision, accuracy, and quantification and detection limits were determined. Physico-chemical and microbiological controls were performed in order to characterize the formulas: 1. Organoleptic properties 2. Quantification of the API 3. Determination of pH 4. Rheological behavior and viscosity 5. Particle size (for suspensions). 6. Optical stability (for suspensions). 7. Microbiological analysis (Ph.Eur) To establish the shelf life, the formulations were stored at three temperatures (4, 25 and 40 °C) for a maximum period of 90 days. The parameters that could change were determined at different times. Biopharmaceutical controls were performed to determine the influence of the excipients on the release (dissolution tests) and absorption (absorption studies through pig small intestine) processes of the API. Obtained results ensures the stability of sildenafil, spironolactone, furosemide, methadone and phenobarbital when formulated in oral liquid dosage forms; allowing continuity, quality and efficacy of pediatric therapies such as persistent pulmonar hypertension of the newborn, congestive heart failure, neonatal abstinence syndrome and neonatal seizures, as appropriate.

Background: Aminoglycoside antibiotics are commonly used in paediatric clinical practice, especially for the treatment of neonatal sepsis and pulmonary exacerbations in cystic fibrosis (CF). However, megalin-mediated endocytosis of the aminoglycosides by renal proximal tubule epithelial cells leads to toxicity, and may result in acute kidney injury and chronic kidney disease. Current approaches to identify and prevent toxicity are limited. Several novel biomarkers have shown utility in preclinical studies for the identification of aminoglycoside-induced nephrotoxicity, but clinical data and an understanding of their clinical utility is lacking. The potential of statins to prevent aminoglycoside-induced nephrotoxicity by inhibition of megalin-mediated endocytosis has been previously demonstrated in vitro and in a rat model, but its potential in man is unclear. Aims: Firstly, to investigate the utility of novel urinary biomarkers for the early identification of aminoglycoside-induced nephrotoxicity in children. Secondly, to develop a novel intervention using statins to prevent aminoglycoside-induced nephrotoxicity in children with CF. Methods and Results: Urine samples were collected from 41 premature neonates at least once per week, and daily during courses of gentamicin. Three urinary biomarkers were measured using Luminex-based (Kidney Injury Molecule-1 (KIM-1) and Neutrophil Gelatinase-associated Lipocalin (NGAL)) and colorimetric assays (N-acetyl-β-D-glucosaminidase (NAG)). All three biomarkers were elevated during treatment with gentamicin, but when adjusted for potential confounders, only the elevation in KIM-1 remained significant (mean difference from not treated, 1.35ng/mg urinary creatinine; 95% CI 0.05-2.65). Electrochemiluminescent assays for both KIM-1 and NGAL were validated, and were compared to Luminex-based assays by analysing samples from healthy children in the UK (n=120) and the US (n=171). 95% reference intervals for both biomarkers were derived using quantile regression. Urine samples were collected from a cohort of children with cystic fibrosis (n=158) at outpatient clinic appointments and during exposure to tobramycin. Biomarkers were measured using the validated electrochemiluminescent assays. Elevations in both KIM-1 and NGAL (median peak fold-change was 2.28 (IQR 2.69) and 4.02 (IQR 7.29) respectively) were observed during exposure to tobramycin. In a multiple regression model, baseline KIM-1 was associated with the number of previous courses of IV aminoglycoside (p < 0.0001; R2=0.11). An in vitro model of aminoglycoside-induced nephrotoxicity was developed using a conditionally immortalized proximal tubule epithelial cell line (ciPTECs). Dose and time-dependent toxicity was demonstrated with neomycin, gentamicin, and tobramycin (from most to least potent). In rats, the addition of rosuvastatin significantly reduced nephrotoxicity compared to gentamicin alone (p < 0.01). In guinea pigs, dose-dependent inhibition of gentamicin-induced nephrotoxicity was seen with rosuvastatin (at a minimum concentration of 0.94mg/kg/day, p < 0.0001), but not with simvastatin. In vitro models demonstrated that neither rosuvastatin nor atorvastatin had any effect on the minimum inhibitory concentration of tobramycin for Pseudomonas aeruginosa. Conclusion: Urinary KIM-1 has shown potential as a biomarker of both acute and chronic proximal tubular injury associated with exposure to aminoglycosides in children. Inhibition of aminoglycoside-induced nephrotoxicity by statins was demonstrated in further animal models, allowing the selection of a statin and dose (rosuvastatin 10mg) which have been taken forward into a clinical trial which will test this hypothesis in children with CF, utilising urinary KIM-1 as the primary outcome measure.

Chest physiotherapy is integral to the management of mechanically ventilated children and previous research has confirmed that chest wall vibrations are the manual techniques used most frequently by physiotherapists in this population. Chest wall vibrations involve the application of a compressive force to the chest during expiration, with the aim of removing accumulated secretions and improving lung aeration. However, these techniques are largely unquantified and may vary greatly between practitioners and clinical units, with any significance of such variability remaining unknown. In order to evaluate the effectiveness of any therapy it is important to have a means of quantifying the treatment. It is challenging to measure techniques which involve manual contact between the therapist and patient, and at the inception of this project no means existed of directly measuring the force applied through the hand during treatments. The effectiveness of chest physiotherapy in mechanically ventilated patients is likely to be influenced by the interactions between different treatment components, such as the magnitude and pattern of the chest wall vibrations and the accompanying lung inflations. It is therefore essential to assess both the forces applied during the vibrations with the simultaneous changes in air flow, recording the ventilatory pattern throughout the treatment. The study hypotheses were: 1. It is possible to create a technique to measure chest wall vibration forces during clinical treatments, and to relate such forces to simultaneous changes in respiratory flows, volumes and pressures 2. Maximum and mean force applied during chest wall vibrations increase with the size and age of the child 3. Manual lung hyperinflations with chest wall vibrations result in an increase in peak expiratory flow above that observed during baseline mechanical ventilation 4. After adjusting for inflation volume, application of chest wall vibrations result in an increase in peak expiratory flow above that obtained during manual lung inflations alone The primary objectives of this research were to: 1. Develop a method of quantifying chest wall vibration forces and a means of evaluating simultaneous changes in force with those of respiratory flow and pressure in ventilated infants and children of all ages 2. Estimate the variability over time, within and between individual physiotherapists when treating the same and different subjects with chest wall vibrations 3. Conduct a study to: i) Assess the feasibility of measuring force and respiration in a population of critically ill, mechanically ventilated children ii) Characterise the magnitude and pattern of forces applied during chest wall vibrations and evaluate the direct effects of these manoeuvres on flow and pressure changes in the lungs iii) Determine the relative contribution of manual lung inflations and chest wall vibrations to any observed increase in expiratory airflow A secondary objective was to explore the short term effects of chest physiotherapy, by recording changes in ventilation, respiratory system mechanics and blood gases following treatment. The thesis comprises four chapters: Chapter 1 contains a comprehensive literature review of published studies demonstrating the current knowledge base of the respiratory problems of mechanical ventilation in children, chest physiotherapy in intensive care and the relationship of chest physiotherapy to normal mechanisms of airway clearance. Chapter 2 describes the process of creating a dynamic force-sensing technique to characterise manual chest physiotherapy, detailing protocol and analysis refinement during pilot force and respiratory data collection. Assessment of the variability within and between physiotherapists is also assessed. Chapter 3 details a clinical study undertaken in intensive care units at Great Ormond Street Hospital for Children NHS Trust, London. The results are presented and interpreted. Chapter 4 discusses the findings of the thesis in relation to earlier research, highlights the strengths and limitations of the current study, interprets the clinical implications of the research and suggests future work.

Despite the scientific, technological and surgical improvements of the past 50 years organ dysfunction following elective paediatric cardiac surgery utilising cardiopulmonary bypass continues to account for increased complications, often leading to a protracted course in hospital with a longer stay in intensive care and the potential for irreversible organ damage long term. Furthermore, paediatric cardiac surgeons are routinely undertaking more complex operations with a shift from palliation to early correction. This has resulted in younger children being subjected to longer periods on the bypass machine with increased effects on vital organs. This thesis describes two clinical studies designed to further assess and characterise peri-operative cardiac, renal and pulmonary function in children undergoing elective cardiac repair at a tertiary referral centre in Scotland, UK. In the first instance a prospective, observational study was undertaken in forty-five children to examine the use of tissue Doppler imaging in the assessment of peri-operative cardiac function, its relationship to myocardial injury and clinical outcome. Tissue Doppler parameters were obtained using a Vivid 7 ultrasound scanner with a 7-MHz probe pre-operatively, on admission to paediatric intensive care and on day one. Myocardial injury was assessed using Troponin-I on the first post-operative day by a commercially available chemiluminescent immunoassay. In twenty children within this group peri-operative renal function was also investigated using standard estimates of glomerular filtration rate, namely creatinine clearance measured by the kinetic Jaffe method during the first and second twelve hour post-operative periods, in comparison to serum creatinine and the novel biomarker cystatin C. Routine plasma retained pre-operatively and on days 0, 1, 2 and 3 post-operatively was used to measure serum cystatin C and creatinine using a particle-enhanced nephelometric immunoassay and the Roche Creatinine Plus enzymatic assay respectively. The association between cystatin C and recorded perfusion parameters including bypass duration, pump flow, haematocrit, oxygen delivery and Troponin-I was investigated. Peri-operative pulmonary function was evaluated through a phase IV, randomised, double-blind, placebo controlled trial. In total, twenty four children were randomised to receive oral sildenafil or equivalent volume placebo four times the day before surgery. Blood samples were collected peri-operatively to measure serum cyclic guanosine monophosphate with a commercially available competitive enzyme immunoassay. Haemodynamic data and echocardiography were acquired at two and twenty four hours post-operatively including pulmonary vascular resistance index and bi-ventricular contractility. Post-operative oxygenation was also determined at the same time by oxygen delivery and oxygenation index. In Chapter 2, peri-operative cardiac function as assessed by tissue Doppler imaging was examined. The results of this study demonstrated that pre-operatively, bi-ventricular systolic function in the study group was reduced compared with normal controls, displaying a significant step-wise decrease with increasing complexity of lesion. This picture persisted post-operatively predominantly in the right ventricle and was significantly associated with the extent of myocardial injury. Impaired peri-operative left ventricular function correlated with clinical outcomes. In Chapter 3, peri-operative renal function as assessed by cystatin C and its association with parameters of perfusion was examined. The results of this study demonstrated that in comparison to serum creatinine, cystatin C had a superior correlation with glomerular filtration rate in the early post-operative period. An elevated level of this biomarker was significantly associated with bypass duration, minimum pump flow and post-operative myocardial injury. Haematocrit was not directly linked to renal dysfunction in this study although evidence of a critical dysoxic threshold within the kidney was suggested indirectly through oxygen delivery calculations. In Chapter 4, peri-operative pulmonary function and vascular reactivity in association with the pre-operative administration of oral sildenafil (0.5mg/kg, six hourly) was examined. The results of this trial demonstrated that compared to placebo, pre-operative sildenafil resulted in modest elevations of serum cyclic guanosine monophosphate, limited effects on pulmonary vascular resistance index, significant reductions in peri-operative bi-ventricular contractility, significant reductions in post-operative oxygen delivery and a trend for increasing ventilatory support. In summary, the current thesis has demonstrated that in children undergoing corrective cardiac surgery peri-operative bi-ventricular function can be accurately assessed by tissue Doppler imaging which to date has had limited use in this patient group. With regards to renal function, cystatin C was shown to be a better estimate of glomerular filtration rate and a more sensitive marker of early renal dysfunction in children after surgery. Furthermore, cystatin C identified a transient post-operative renal impairment, the magnitude of which was associated with duration of bypass, pump flow and myocardial injury. In relation to pulmonary function, this research identified that pre-operative administration of oral sildenafil to children undergoing cardiac surgery produced limited effects on pulmonary vascular resistance but was associated with reduced ventricular contractility and post-operative oxygenation raising significant concerns over its routine clinical use.

Exogenous surfactant therapy has dramatically improved survival in extremely preterm infants, however the turnover of exogenous and synthesis of endogenous surfactant components are still poorly understood in this group. Additionally there is evidence for this patient group that improving nutrition improves long-term outcomes in respiratory function, growth and neurodevelopment. Phosphatidylcholine (PC) is the dominant phospholipid in both surfactant and in plasma and can be synthesised from choline by one of two pathways: the CDPcholine pathway, which is present in all nucleated cells, or by three sequential methylations of phosphatidylethanolamine in the PEMT pathway, which is localised to hepatocytes and is the primary source of polyunsaturated PC species and de novo synthesis of choline. This study quantified choline phospholipid metabolism and pulmonary surfactant kinetics in preterm infants in vivo. Children aged between 23 and 28 weeks gestation and in receipt of exogenous surfactant were intravenously infused with [methyl-D9]choline chloride within 48 hours of birth. Lipid extracts from sequential plasma and endotracheal aspirate samples were then analysed by electrospray ionisation tandem mass spectrometry (ESIMS/ MS). Fractional incorporation into newly synthesised PC species is demonstrated rapidly in plasma samples at a higher rate than previously reported in adults, indicating a high level of hepatic activity for CDP-choline. Analysis of the PC species derived from the PEMT pathway shows significantly lower flux in this pathway than reported in adults. Finally incorporation into surfactant PC species is very low initially before rising slowly over several days and with the rapid changes in other acidic phospholipids suggests a rapid recycling of components of the exogenous surfactant not equilibrating with the CDP-choline pathway thereby providing evidence for the first time of differing rates of exogenous surfactant recycling versus de novo synthesis in the human preterm infant. This study proves that the technique works in the clinical environment, is sensitive and rapid enough to provide data in a clinically relevant timeframe, opening the possibility for translational use to identify biomarkers for disease progression.

One new treatment strategy for children with hemiplegic cerebral palsy (CP) is constraint-induced movement therapy (CIMT). CIMT combines restraint of the less affected upper extremity and intensive exercise with the affected limb. CIMT has been shown to be effective in adults following stroke but it is not clear whether or not CIMT can readily be incorporated into clinical practice either with adults or children. An intervention that may be more practical involves the restraint element of CIMT without additional exercise (Forced use therapy-FUT). FUT has been only sparsely investigated, especially in children with CP. Different versions of CIMT protocols have been suggested as being „child-friendly‟ but identifying a practical and effective protocol remains challenging. Part of a child-friendly protocol includes identification of the most appropriate type of constraint, as different splints have been used for different populations without justification of their selection. In this project, the aim was to identify the most appropriate splint from children‟s and parents‟ perspective as reflected by effectiveness and adherence to home-based FUT (feasibility study) and to investigate the functional effects of a modified version of CIMT (mCIMT) (effectiveness study) that was designed based on the findings of the feasibility study. A further aim of the study was to compare the effect of additional functional activities and feedback with constraint alone. Two questions emerged as being important during the course of the project; the first addressed poor recruitment to the effectiveness study and explored parents and therapist‟ views on the practicality and effectiveness of both the classic paediatric protocol and the one suggested by the present study. The second was to provide insight into the physiological effects of CIMT or other treatments that might explain variations in response. In this study a test using the lateralised readiness potential (LRP) component of the EEG that was appropriate for young children was developed and evaluated with a small sample of unimpaired children and children with CP.

Severe congenital heart disease (CHD) is diagnosed in the United States 147.4 times per 100,000 live births, excluding still births and abortions^1. With the advancement of diagnostic methods, prenatal care, and screening modalities, the total CHD birth prevalence has increased substantially^2. In turn, this increases the number of cardiac surgery cases. With the advancement of technology and cardiac surgery, smaller and younger patients are undergoing more complex cardiac procedures that involve cardiopulmonary bypass (CPB). Neonates and infants undergoing CPB are susceptible to adverse effects of CPB on the coagulation cascade due to their smaller weight and hematologic immaturity^3,4. In addition to these physiological issues in neonates and infants, CPB decreases circulating coagulation factors and anti- thrombin III levels to 50% and platelet counts to 70%^5, which can contribute to the post-operative bleeding.During CPB, neonates' and infants' coagulation factors become extremely diluted causing multiple coagulation defects^6. Optimizing the CPB circuit volume and the use of anti-fibrinolytic, packed red blood cells (pRBCs), platelets, cryoprecipitate, and ultrafiltration are among the most widely used methods in preserving and aiding coagulation factors^3,7-9. Another method of improving hemodilution-related coagulation dysfunction bleeding is by transfusing Fresh Frozen Plasma (FFP)^10. However, there are only a small number of articles focusing on the effect of FFP in post-operative bleeding in neonates and infants following complex cardiac surgery with CPB. I postulate that adding FFP during CPB will lower the possibility of patients to experience post-operational bleeding, thus, shortening their length of stay (LOS).

La tuberculosi és una infecció bacteriana causada per un micobacteri anomenat Mycobacterium tuberculosis. Actualment és la primera causa mundial de mortalitat causada per un agent infecciós fins i tot per sobre de la Síndrome d’Immunodeficiència Adquirida (SIDA). Segons l’informe anual sobre tuberculosi realitzat per l‘Organització Mundial de la Salut (OMS), a l’any 2016 10,4 milions de persones van emmalaltir de tuberculosi, 1,3 milions van morir per aquesta malaltia dels quals 130.000 foren nens. El tractament d’elecció per a la tuberculosi infantil és la combinació de rifampicina, isoniazida i pirazinamida. Actualment, no existeix cap medicament al mercat que contingui una combinació d’aquests tres principis actius adaptat a les necessitats d’un pacient pediàtric, és a dir, la forma farmacèutica i la dosificació existent està indicada per pacients adults. Aquest fet fa que l’adherència terapèutica dels pacients pediàtrics sigui baixa, i com a conseqüència, l’èxit del tractament i les probabilitats de curació també ho siguin. La inexistència de tractaments destinats al sector pediàtric es principalment conseqüència de la incompatibilitat que presenten els tres principis actius en medi líquid aquós. La isoniazida conjuntament amb la rifampicina en medi aquós desencadena una reacció d’hidròlisi que produeix la degradació de la rifampicina. A més a més, l’addició de pirazinamida a una formulació que contingui els altres dos principis actius, augmenta la degradació de la rifampicina degut a que la pirazinamida catalitza la reacció que es dona entre rifampicina i isoniazida. L’objectiu principal d’aquesta tesi es obtenir un nou medicament en forma farmacèutica líquida d’administració oral que permeti dosificar de manera conjunta, senzilla i individualitzada, la combinació de tres dels principis actius (isoniazida, rifampicina i pirazinamida) més utilitzats pel tractament de la tuberculosis en població pediàtrica. Amb la finalitat de conèixer en profunditat les característiques físiques, químiques i tecnològiques de cada principi actiu, es realitzen estudis de solubilitat, determinació de la mida de partícula, espectrofotometria UV-Vis, espectroscòpia d’infraroig (IR), ressonància Magnètica Nuclear (RMN), difracció per Raig X i determinació d’ incompatibilitats entre principis actius mitjançant calorimetria diferencial d’escombratge (DSC). També es realitzen estudis de preformulació i formulació on s’estudien les característiques físico-químiques i galèniques dels excipients viables per a la forma farmacèutica proposada (suspensió oral). Considerant la degradació que pateix la rifampicina amb isoniazida i pirazinamida en medi aquós, es tria una base oliosa com a vehicle alternatiu. Es realitzen proves amb diferents excipients (agents suspensors, dispersants, antiadherents, emmascarants i saboritzants) amb la finalitat de millorar les propietats galèniques i organolèptiques de la suspensió. Es realitzen un total de 15 referències diferents i s’obté una fórmula definitiva i una tècnica d’elaboració. Per valorar i comparar les diferents formulacions es defineixen uns paràmetres a estudiar (viscositat, mida de partícula, característiques organolèptiques i propietats de la suspensió) i s’assigna un valor numèric a cadascun d’ells, evitant així resultats subjectius. Dels resultats obtinguts en els estudis de formulació, s’obté una formulació i una tècnica d’elaboració. Es desenvolupa i valida un mètode d’anàlisi que permet la detecció i quantificació conjunta dels tres principis actius objecte d’estudi i dels seus productes de degradació mitjançant cromatografia líquida d’alta resolució. Es realitzen estudis d’estabilitat preliminar per obtenir dades orientatives de la fórmula definitiva i estudis d’estabilitat definitiva segons marquen les guies ICH. Finalment s’obté una suspensió de preparació extemporània de rifampicina, isoniazida i pirazinamida estable durant 27 dies sota condicions de refrigeració (5 ºC ± 3 ºC) i de bon gust, la qual s’adapta perfectament a les necessitats posològiques i d’administració de la població infantil.<br>Tuberculosis is a bacterial infection caused by Mycobacterium tuberculosis. It is currently the world's leading cause of mortality caused by an infectious agent even above the Acquired Immunodeficiency Syndrome (AIDS). The first-line treatment for tuberculosis in pediatric population is the combination of rifampicin, isoniazid and pyrazinamide. Currently, there is no medication in the market with a combination of these three active pharmaceutical ingredients adapted to the needs of the pediatric patients. This situation causes a decrease in the therapeutic adherence and consequently in the success of the treatment. The lack of treatment for the pediatric sector is due to the incompatibility of the three active pharmaceutical ingredients in aqueous medium. Isoniazid in combination with rifampicin triggers a hydrolysis reaction that causes the degradation of rifampicin. Besides, the addition of pyrazinamide to a formulation that contains the other two active ingredients increases the degradation of rifampicin due to the fact that pyrazinamide catalyzes the reaction between rifampicin and isoniazid. The main objective of this investigation is to obtain a new oral medication in a liquid form that allows the dosing of the three active ingredients combination (isoniazid, rifampicin and pyrazinamide) in a simple and individualized way. A physical, chemical and technological study of each active ingredient was performed in order to know the individual properties of them. Preformulation and formulation studies were developed obtaining a final formulation and a manufacturing procedure. An analytical method was developed and validated. The method allows the joint detection and quantification of the three active pharmaceutical ingredients and its degradation products through high resolution liquid chromatography. Preliminary stability studies were carried out in order to obtain data for the final formulation. Final stability studies were performed according to the ICH guidelines. A 27 days’ stable suspension under cooling conditions (5 ºC ± 3 ºC) of rifampicin, isoniazid and pyrazinamide was obtained. The suspension, which has a good taste, is perfectly suited to the posology and administration needs of the child population.

The use of antiretroviral therapy (ART) during pregnancy and lactation has significantly reduced the rate of mother-to-child transmission (MTCT) of HIV. However, pregnancy is known to affect the pharmacokinetics of many drugs, including key antiretroviral (ARV) drugs. In addition, ARV use during lactation raises questions about unintended exposure of breastfed infants to maternal drugs through breast milk. For drugs with significant genetic contribution to observed pharmacokinetic variability, we hypothesised that polymorphisms in drug disposition genes may accentuate or attenuate pregnancy-induced changes and/or breastfed infants’ exposure. HIV positive pregnant women and nursing mothers taking efavirenz (EFV)- or nevirapine (NVP)-based ART were recruited from three hospitals in Benue State, Nigeria. A novel strategy involving a preliminary pharmacogenetic association study was used to investigate the magnitude of pregnancy-induced changes in EFV and NVP pharmacokinetics in women stratified by single nucleotide polymorphisms (SNPs) in disposition genes. EFV apparent clearance (CL/F) was higher and AUC0-24, Cmax and Cmin were significantly lower in pregnant compared with postpartum women. When stratified based on the SNP with the highest predictive power, pregnant women with CYP2B6 516GG genotype were especially at risk. In the NVP cohort, exposure was also significantly lower in pregnant compared with postpartum women. When stratified based on composite CYP2B6 516G > T and 983T > C genotypes, Cmin was below target in most patients with combined CYP2B6 516GG and 983TT during pregnancy and postpartum. Cmin was below target in at least 50% of pregnant women with one or two variant alleles, compared with 0% in postpartum women. The intensive pharmacokinetics of EFV and NVP in breast milk and pharmacogenetic predictors were described for the first time. Breast milk pharmacokinetic parameters of EFV in breast milk differed significantly between patient groups stratified by CYP2B6 516G > T. The median time averaged milk-to-plasma concentration (M/P) ratio was 1.10 (range: 0.57-1.71) and the paediatric dose weight-adjusted exposure index was 4.05% (1.08-13.8). The resulting infant plasma concentration was influenced by CYP2B6 516G > T, highest up to 8 days of age at 1590 ng/mL (190-4631) and decreased by about 90% in the age stratum 9 days to 3 months. NVP AUC0-12, Cmax and Cmin in breast milk were significantly lower in patients with composite CYP2B6 516GG/983TT than those with at least one variant allele. The M/P ratio was 0.88 (0.74-1.2) and paediatric dose weight-adjusted exposure index was 3.64% (1.99-9.88). Infant plasma concentration differed significantly based on CYP2B6 516G > T/983T > C and CYP3A4 20230G > A (*1G), highest in those exposed through both breast milk and post-exposure prophylaxis compared with either alone. A breastfeeding physiologically-based pharmacokinetic (PBPK) model to predict infant exposure to maternal drugs through breast milk was developed and validated, with over 90% of all individual observed data points within the predictive interval. This thesis presents details about five different studies where these findings were observed. Their clinical implications in the context of current knowledge and practice were also explored.

Lors de cette dernière décennie, le développement de formes pharmaceutiques innovantes permettant d'améliorer l'efficacité, la sécurité et l'acceptabilité des médicaments pédiatriques est en pleine croissance. Les films orodispersibles (ODF) appartiennent à ces nouvelles formes galéniques améliorant la compliance des patients. Ils sont constitués d'une matrice de polymère hydrophile dans laquelle un ou des principe(s) actif(s) (PA) sont dissous ou dispersés. Après dépôt de l'ODF sur la langue ou dans la cavité buccale, la matrice se désagrège libérant le PA pour une action locale ou systémique. Dans cette étude, la mise au point d'ODF, par la méthode de coulée/évaporation de solvant a été explorée afin d'administrer un PA d'intérêt en pédiatrie, la tétrabénazine (TBZ). Les caractérisations physicochimiques et biopharmaceutiques des ODF ont mis en évidence une augmentation de la vitesse et du taux de dissolution de la TBZ induit par son état amorphe. Le système constitué d'un support polymère et d'un PA sous forme amorphe peut être assimilé aux dispersions solides amorphes (SD). Les études réalisées démontrent l'importance de la nature du polymère utilisé pour maintenir les propriétés initiales du système dans le temps. La formation de liaisons hydrogène entre la PA étudié et le polymère est un facteur essentiel pour assurer la stabilité des SD. De plus, l'incorporation de cyclodextrines (CD) prolonge l'état amorphe du PA en générant des liaisons hydrogène avec la TBZ et en l'entourant d'une barrière chimique. Cette association favorise la libération du PA par effet synergique améliorant la biodisponibilité. Cette forme innovante représente un intérêt majeur dans l'amélioration de l'observance dans le cadre d'un traitement pédiatrique<br>During the last decade, various strategies to develop innovating oral dosage forms for pediatric population were investigated in order to improve treatment efficiency, safety and acceptability. Among these new delivery systems, orodispersible films (ODF) present a great potential to enhance patient compliance. In ODF, drug is dissolved or dispersed in a hydrophilic film-forming polymer. Once the ODF is in the mouth, polymeric matrix disintegrates releasing the drug for local or systemic action. In this study, ODF, produced with the solvent casting/evaporation method, were developed to administer a drug of interest for pediatric population, the tetrabetazine (TBZ). Physicochemical and biopharmaceutic characterizations showed that ODF allowed a major improvement of TBZ dissolution profile in simulated saliva, mainly due to the amorphous state of the drug in ODF. ODF were identified as amorphous solid dispersion (SD) composed of both amorphous TBZ and polymer matrix. We demonstrated that the choice of the polymer plays an important role to maintain initial properties of the system and amorphous state stability over the time. H-bonding formation between TBZ and polymer is essential to assure the preservation of TBZ amorphous state. Moreover, the incorporation of cyclodextrins (CD), by generating H-bonding with TBZ, has extended its stability. By synergic effect, this association produces an improvement of drug release leading to promote bioavailability. As they are easy to swallow and allow enhancing treatment efficiency, ODF appear as suitable delivery forms for pediatric patients

Unfractionated heparin (UFH) therapy is frequently used in tertiary paediatric healthcare facilities despite a lack of paediatric-specific research informing the optimal therapeutic intensity, monitoring recommendations or side-effect-profile in infants and children. As a result, the majority of clinical recommendations regarding UFH management in children have been extrapolated from adult evidence. The process of developmental haemostasis, in association with the variable pathogenesis of thromboembolic disease (TED) in children compared to adults, suggests that extrapolation of adult guidelines for UFH management to children is not ideal.<br>This study hypothesised that the process of developmental haemostasis would influence both the action and effect of UFH in children of different ages. This hypothesis was tested by addressing the following aims: 1. To determine the pharmacokinetics (PK) of UFH in children of different ages; 2. To compare the different methods of monitoring UFH in children of different ages; 3. To identify the impact of competitive plasma binding of UFH in children of different ages; 4. To determine the impact of UFH upon tissue factor pathway inhibitor (TFPI) release in children.<br>A prospective cohort study of children receiving a single bolus dose of UFH for primary thromboprophylaxis in the setting of cardiac angiography was conducted. Venous blood samples were collected prior to the UFH, then at 15, 30, 45 and 120 minutes post-UFH bolus. Laboratory assays performed included activated partial thromboplastin time (APTT), anti-Xa assay, anti-IIa assay, thrombin clotting time (TCT), protamine titration and TFPI. Levels of two plasma proteins known to competitively bind UFH (vitronectin and platelet factor 4) were determined and the impact of competitive plasma binding upon UFH activity, as measured by the anti-Xa assay, was quantified. A population approach to pharmacokinetic analysis, based on protamine titration results, was performed using WinNonMix™ Professional 2.0.1 (®1998-2000 Pharsight Corporation, Mountain View, CA, USA). Results were analysed according to the following age-groups: less than one year; one to five years; six to ten years; 11-16 years.<br>Sixty-four children were recruited, ranging in age from six months to fifteen-and-ahalf years. The mean dose/Kg of UFH across the entire cohort was 90.9± 15.5 IU/Kg.<br>Pharmacokinetic model specifications were systematically assessed, investigating the impact of parameter covariates and different error models upon objective function value and/or curve fitting. A first-order kinetic model best fitted the data. This model used weight 0.75 as the covariate of clearance and total weight as the covariate for volume of distribution. Parameter estimates for clearance and volume of distribution both demonstrated variance from adult and small neonatal PK studies of UFH, however methodological differences in PK analysis techniques limited comparisons. The half-life of UFH reported in this study was consistently and significantly shorter than that previously reported for adults, but longer than that reported for neonates.<br>All measures of UFH-effect demonstrated a significant and prolonged increase post- UFH bolus. The mean APTT was 261 seconds 102 ± 25 minutes post-UFH, representing a seven-fold increase from the mean baseline APTT (38 seconds). Anti- Xa assay levels were within the therapeutic range for TED management (0.35 to 0.7 IU/mL), or greater, at every post-UFH bolus timepoint. This prolonged UFH-effect was evident to nearly two hours post-UFH bolus, without concurrent UFH infusion. Age-related differences in UFH-response were evident for anti-Xa, anti-IIa and protamine titration results. Furthermore, during periods of high UFH concentration, the ratio of anti-Xa to anti-IIa activity in children less than one year of age significantly favoured UFH-mediated anti-Xa effect over anti-IIa effect (1.9), compared to teenagers (1.3).<br>This study demonstrated poor correlation between protamine titration and both the anti-Xa assay (r2 = 0.47) and APTT (r2 = 0.56). Use of the anti-Xa assay (0.35 to 0.7 IU/mL) or protamine titration assay (0.2 to 0.4 IU/mL) to establish APTT-based reference ranges for therapeutic management of TED resulted in APTT ranges with upper limits greater than 250 seconds.<br>No age-related quantitative differences in plasma levels of vitronectin or platelet factor 4 were identified across the childhood years. The addition of dextran sulphate (DS) to ex vivo study samples demonstrated no change in anti-Xa activity in samples collected within 20 minutes of UFH bolus, however a significant increase in anti-Xa activity following the addition of DS was evident at all later timepoints post-UFH bolus.<br>The measurement of TFPI before and after a single bolus dose of UFH demonstrated children have a similar immediate increase in TFPI activity following intravenous UFH compared to adults. However, the children in this series demonstrated a significantly prolonged level of increased TFPI activity, out to 102 ± 25 minutes post-UFH, compared to that reported in adult patients.<br>This study has developed the first paediatric-specific PK profile of UFH and has elucidated a number of age-dependent UFH-mechanisms of action that contribute to the previously reported age-dependent response to UFH in children. The results of this study support the hypothesis that developmental haemostasis influences both the action and effect of UFH in children of different ages.

Passive exposure of children to drugs is common, but difficult to ascertain as direct studies are in many cases not possible, and currently available indirect measures of drug exposure, such as maternal reports, are likely to be inaccurate. Novel, indirect methods to evaluate drug exposure in the uterus and early life are needed, and may provide risk estimates that can be later correlated with clinical outcomes. In the studies presented here, I have applied novel methods such as measurement of hair drug concentrations and population pharmacokinetics modeling and simulation to evaluate fetal and infant exposure to drugs and potential associated risks. Testing for methamphetamine allowed demonstration, for the first time, that it freely crosses the human placenta. In contrast, analysis of paired maternal–infant hair showed limited cocaine placental transfer, in agreement with animal models. Results of hair tests from children found in marihuana grow houses and other drug operations showed that passive exposure tends to be higher in infants, likely due to higher dependence on, and proximity to care givers. We also demonstrated the importance of measuring drug metabolites to distinguish between systemic exposure to MDMA and simple external hair contamination secondary to drug present in the home environment. Finally, we developed a population pharmacokinetics and simulation approach to accurately estimate drug excretion into breast milk. This novel technique was applied to fluoxetine and to nifurtimox. Use of our approach allowed us to define, for the first time, the limited extent to which fluoxetine and nifurtimox would be expected to cross into breast milk and estimate potential degree of exposure of breastfed infants. In summary, results presented here support the value of these novel methods for the evaluation of fetal and infant drug exposure and suggest a promising value in estimating risks to children passively exposed to drugs.

L’immunosuppression optimale après greffe d’organe solide est une balance délicate et propre à chaque individu entre le risque de rejet et les risques liés à une surexposition au traitement immunosuppresseur. L’évaluation de la fonction résiduelle des lymphocytes T après stimulation par un mitogène (pharmacodynamie effective) devrait permettre de mesurer l’effet direct des médicaments immunosuppresseurs sur leur cible. Nous avons étudié différents paramètres de pharmacodynamie effective chez 34 receveurs pédiatriques de greffe d’organes solides traités par tacrolimus et mycophénolate. Les tests proposés dans ce travail sont adaptés au milieu pédiatrique et à une réalisation en temps réel. La quantification du CD25 parmi les CD4 activés par l’OKT3 permet de distinguer deux groupes de patients selon leur degré d’immunosuppression. L’âge médian est plus bas et la concentration plasmatique médiane en MPA plus élevée dans le groupe de patients plus fortement immunosupprimés. L’étude des paramètres immunologiques pouvant influencer la réponse (sécrétion des interleukines, proportion des sous-populations lymphocytaires CD4, CD8, T naïfs et Trég) ainsi que l’étude du pouvoir de restauration de la fonction lymphocytaire par l’Il-2, la guanosine ou la xanthosine, ne permettent pas de mieux comprendre les variabilités interindividuelles observées. Ces résultats devront être confirmés sur une cohorte plus grande de patients afin de juger de leur intérêt en pratique clinique.<br>Optimal immunosuppression following solid organ transplantation is unique to each individual and requires a balance between risks of rejection and overexposure to immunosuppressive therapy. The evaluation of residual function of T lymphocytes after mitogen stimulation (effective pharmacodynamic monitoring) should allow measurement of the direct effect of immunosuppressive drugs on their target. We studied various parameters of effective pharmacodynamic monitoring in 34 paediatric patients receiving solid organ transplants and treated with tacrolimus and mycophenolate (MPA). The tests proposed in this work are adapted to the paediatric setting in real time. Quantification of CD25 among CD4 cells activated by OKT3 can differentiate two groups of patients according to their degree of immunosuppression. Median values for age and MPA plasma concentration are lower and higher, respectively, in the patient group most heavily immunosuppressed. Neither study of the parameters that may influence the response (secretion of interleukins, proportion of lymphocyte subpopulations CD4, CD8, naive and regulatory T cells) nor study of the restoration of basal cell function brought about by Il2, guanosine or xanthosine, helped to explain the observed inter-individual variability. These results should be confirmed in a larger cohort of patients in order to test their relevance in clinical practice.

Acute Lymphoblastic Leukemia (ALL) is an aggressive hematologic tumor and is the most common malignancy in children (Horton and Steuber 2014). This disease is characterized by the infiltration of bone marrow by malignant immature lymphoid progenitor cells and is invariably fatal without treatment. Although multi-agent combination chemotherapy is curative in a significant fraction of ALL patients, treatment currently fails in approximately 20% of children and up to 50% of adults with ALL, making relapse and drug resistance the most substantial challenge in the treatment of this disease(Fielding, Richards et al. 2007, Aster and DeAngelo 2013). Understanding what causes treatment failure is of great medical importance as second line therapies also fail in the majority of relapse T-cell ALL (TALL) patients (Fielding, Richards et al. 2007, Aster and DeAngelo 2013). Using next-generation sequencing to compare the genomes of tumors before and after therapy, mutations in gene cytosolic 5’-nucleotidase II (NT5C2) were discovered in 19% of pediatric samples with relapsed T-ALL(Tzoneva, Carpenter et al. 2013). Preliminary structure function analysis and subsequent in vitro experimental nucleotidase activity assays confirmed that these mutations lead to hyperactive NT5C2 protein. Furthermore, NT5C2 mutant proteins conferred resistance to 6-mercaptopurine and 6-thioguanine chemotherapy drugs when expressed in ALL lymphoblasts, suggesting NT5C2 is responsible for the inactivation of nucleoside-analog chemotherapy drugs. In order to assess the ability of these mutations to lead to novel inhibitor schemes, the functional impact of each mutation was analyzed through robust structure function methods. The result of this in silico analysis, is the identification of a potential allosteric regulatory mechanism of negative feedback inhibition never before described. Most notably, the majority of NT5C2 mutations identified have characteristics that suggest they abrogate the function of this proposed mechanism, yielding a novel viable target for the development of allosteric inhibitors specific for constitutively active NT5C2 mutant proteins. Overall these findings support a prominent role for activating mutations in NT5C2 and chemotherapy resistance in ALL, and highlight new avenues for relapsed ALL therapy development in the future.

Introduction : La tolérance induite par l’utilisation prolongée des opiacés peut se traduire par un syndrome de sevrage aux opiacés (SDSO). Il n’existe aucun consensus sur la méthode idéale de sevrage des opiacés pour prévenir le SDSO chez la clientèle des soins intensifs pédiatriques (SIP). L’objectif de cette étude était de comparer l’efficacité de deux stratégies de sevrage des opiacés, à savoir la méthadone et la morphine administrées par voie entérale, à prévenir le SDSO. Devis : Essai clinique randomisé à double aveugle chez les enfants sous ventilation mécanique hospitalisés aux SIP. Méthode : Nous avons comparé la durée totale de sevrage, l’incidence et la sévérité du SDSO chez les enfants à risque au moins modéré de SDSO sevrés avec la méthadone et la morphine entérales. Les enfants inclus étaient ceux hospitalisés au Centre Hospitalier Universitaire Sainte-Justine ou au Centre Mère-Enfant Soleil de Québec entre le 1er novembre 2003 et le 31 mai 2009. Résultats : Quarante-huit patients (22 groupe méthadone et 26 groupe morphine) ont été inclus et 30 patients ont complété le protocole de sevrage (16 groupe méthadone et 14 groupe morphine). La durée médiane de sevrage était de 5.4 jours dans le groupe méthadone comparativement à 5.8 jours pour le groupe morphine (p=0.49). Il n’y avait pas de différence dans l’incidence du SDSO (62.5% versus 42.9%; p=0.46), et dans sa sévérité (12.5% versus 14.3% de SDSO sévère; p=0.62). Conclusion : L’efficacité d’un sevrage standardisé des opiacés par la méthadone était comparable à celle de la morphine.<br>Background : The prolonged use of opioids has been associated with opioid tolerance and weaning is necessary to prevent opioid withdrawal symptoms (OWS). Little research exist for an ideal effective opioid taper to reduce the prevalence of OWS. This study aim to compare the effectiveness of two opioid taper strategies, enteral’s methadone and morphine, in preventing the occurrence of OWS among pediatric intensive care patients. Design: Double-blinded randomized controlled trial in mechanically ventilated children (MVCs) hospitalized in 2 pediatric intensive care units (PICU). Methods: Eligible patients were MVCs at moderate risk of OWS admitted in PICU of the Centre Hospitalier Universitaire Sainte-Justine or the Centre Mère-Enfant Soleil de Québec between November 1, 2003 and May 31, 2009. We assessed the total weaning duration, the OWS’s incidence and the OWS’s severity in a methadone’s and a morphine’s taper schedule. Results: Forty-eight patients were included, 22 in the methadone group and 26 in the morphine group and 30 patients completed the weaning protocol (16 methadone and 14 morphine). The median duration of weaning was 5.4 days among methadone’s patients as opposed to 5.8 days among morphine’s group (p=0.49). There was no statistical difference between groups for OWS’s incidence (62.5% vs 42.9%; p=0.46), nor for its severity (12.5% vs 14.3% of severe OWS; p=0.62). Conclusion: The use of a standardized opioid weaning protocol with enteral methadone was as effective as the enteral morphine one’s to prevent OWS. Further studies are needed to determine an ideal opioid taper to reduce OWS.

orientação: Liliana Pires Antunes Castanheira de Carreiro Mendes<br>A intervenção do farmacêutico clínico na população pediátrica implica uma abordagem terapêutica específica, consoante a idade e o fármaco considerado. A pesquisa da dose e regime posológico; a escolha da forma farmacêutica adequada; as possíveis técnicas de administração, bem como a farmacovigilância implícita, são alguns dos cuidados a ter em conta, de modo a garantir a segurança e eficácia do tratamento. Tendo em conta todos estes fatores, a União Europeia tem vindo a reconhecer este grupo como vulnerável e distinto da população adulta. Ao longo do tempo tem-se assistido à criação de normas legislativas, que vão ao encontro das necessidades da população pediátrica; e incentivos à indústria, por forma a promover o aumento da produção industrial dos medicamentos. Assim compreende-se a importância do farmacêutico, como profissional de saúde adequado na avaliação de todos os fatores inerentes à classe pediátrica, tendo um papel vital na terapêutica da mesma. Este trabalho tem como objetivo abordar de uma forma geral o papel do farmacêutico clínico na terapêutica pediátrica. Neste âmbito, são tidos em conta os critérios de administração de medicamentos em crianças, nomeadamente a imaturidade física e psíquica e, as características anatomofisiológicas e metabólicas, não esquecendo, que do ponto de vista farmacológico, a criança apresenta mecanismos farmacocinéticos e farmacodinâmicos próprios.<br>The clinical pharmacist intervention over the pediatric population, implies a specific approach, considering the age and the specific drug. To ensure the safety and efficacy of treatment, it is necessary the pharmacis study the adequated dose , dosing regime and dosage form know the several management techniques, and do the implied pharmacovigilance. Considering all these factors, the European Union has been recognising the group as vulnerable and distinct from the adult population. Over time, there has been witnessed the creation of legislative norms, which meet the needs of the pediatric population; and incentives to the industry, to promote an increase in pediatric medicines industrial production . Therefore, this highlights the importance of the clinical pharmacist, as the appropriate health professional for the evaluation of all factors involving the pediatric population. The pharmacist have a vital role in the pediatric therapeutics. This work aims to generally address the role of the clinic al pharmacist in the pediatric therapeutics. In this context, are addressed the drugs administering criteria for children, such as the physical and mental immaturity, the anatomophysiologica l and metabolic characteristics. As well the fact of the children present their own pharmacokinetic and pharmacodynamic mechanism.

Les procédures impliquant des aiguilles sont la plus importante source de douleur chez les enfants. Considérant qu’il est impossible d’éliminer complètement la douleur ressentie lors de procédures douloureuses, il est de la responsabilité professionnelle de l’infirmière d’assurer sa gestion à l’aide d’interventions non-pharmacologiques et/ou pharmacologiques. Les interventions actuellement disponibles pour le soulagement de la douleur procédurale des enfants nécessitent beaucoup de temps ou de personnel, ce qui représente des barrières à leur implantation dans les services d’urgence. Par conséquent, l’utilisation d’une intervention non-pharmacologique rapide et facile d’utilisation pourrait permettre de pallier ces contraintes. À cet effet, un dispositif combinant le froid et la vibration (Buzzy) a été développé dans l’objectif d’optimiser le soulagement de la douleur procédurale pédiatrique. Ce dernier repose sur deux mécanismes permettant la modulation du message douloureux, soit la théorie du portillon et les contrôles inhibiteurs nociceptif diffus. Le dispositif Buzzy semble donc être une avenue prometteuse pour surmonter les obstacles reliés à la gestion de la douleur lors de procédures impliquant des aiguilles dans les services d’urgence. Le but principal de cette étude était de déterminer si un dispositif combinant le froid et la vibration (dispositif Buzzy) était considéré comme étant non-inférieur à un anesthésique topique (lidocaïne liposomale 4%) pour la gestion de la douleur d’enfants lors de procédures impliquant des aiguilles dans les services d’urgence. Cet essai clinique randomisé de non-infériorité parallèle à deux groupes a été mené dans le service d’urgence d’un centre hospitalier universitaire pédiatrique (CHU Sainte-Justine, Montréal, Canada). Un total de 352 enfants âgés entre 4 et 17 ans a été recruté et 346 ont été randomisés, soit au groupe expérimental (dispositif Buzzy=172) ou au groupe contrôle (anesthésique topique=174). Pour les participants ayant été assignés au groupe expérimental, le dispositif Buzzy a été appliqué à environ 5 cm au-dessus du site d’insertion et a été maintenu en place tout au long de la procédure. Pour les participants ayant été assignés au groupe contrôle, un anesthésique topique (lidocaïne liposomale 4%) a été appliqué au niveau du site d’insertion 30 minutes avant la procédure. Selon l’analyse en intention de traiter, la différence moyenne de douleur procédurale entre les deux groupes à l’étude (dispositif Buzzy : 3,92  3,13; anesthésique topique : 3,27  3,02) était de 0,64 (95%IC -0,10 à 1,26) sur l’échelle de mesure Color Analogue Scale (0-10). Ceci démontre donc que le dispositif Buzzy n’est pas considéré comme étant non-inférieur à l’anesthésique topique. En ce qui concerne la détresse procédurale, aucune différence statistiquement significative n’a été décelée avec les deux échelles de mesures utilisées (Procedure Behavior Check List : p=0,104 ; Children’s Fear Scale : p=0,421). Il n’y avait également aucune différence statistiquement significative en ce qui concerne le succès de la procédure au premier essai (p=0,489) ainsi que la mémoire de la douleur 24 heures après la procédure (p=0,346). De plus, aucun effet secondaire n’a été enregistré pour les participants ayant utilisé le dispositif Buzzy et seulement un évènement est survenu chez un participant ayant reçu l’anesthésique topique. Enfin, les parents des deux groupes ont rapporté être satisfaits avec l’intervention reçu par leur enfant (p=0,257) et la majorité des infirmières (65,0%) ont manifesté une préférence pour le dispositif Buzzy. Le dispositif Buzzy n’est pas considéré comme étant non-inférieur à un anesthésique topique pour la gestion de la douleur d’enfants lors de procédures impliquant des aiguilles. Toutefois, considérant que les anesthésiques topiques sont sous-utilisés dans les services d’urgence, le dispositif Buzzy représente une alternative intéressante à cette méthode pharmacologique nécessitant un temps d’application. Par conséquent, le dispositif Buzzy pourrait être davantage transférable à la pratique et les cliniciens pourraient possiblement l’intégrer plus facilement dans leur routine quotidienne.<br>Needle-related procedures are considered as the most important source of pain in children in hospital settings. It is now recognized that even minor procedures can result in physiological, psychological and emotional consequences. For these reasons, management of children’s pain and distress through pharmacological and/or non-pharmacological intervention is essential. Healthcare professionals working in the Emergency Department (ED) setting face particular challenges regarding procedural pain management related to their work environment. Time constraints, heavy workload, and busy environment represent barriers to the use of available interventions for pain management during needle-related procedures. Therefore, the use of a rapid, easy-to-use intervention could improve procedural pain management practices in the context of the ED. As such, the Buzzy device, which is a bee-shaped device combining vibration and cold, seems to be a promising alternative. The theoretical bases of this device are the Gate Control Theory and the diffuse noxious inhibitory controls, both generating the modulation of pain. The primary objective of this study was to determine if a device combining cold and vibration (Buzzy device) was considered as non-inferior (no worse) to a topical anesthetic (liposomal lidocaine 4% cream) for pain management in children undergoing needle-related procedures in the ED. This randomized, controlled, non-inferiority trial with two parallel groups was conducted in the ED of a university pediatric tertiary hospital center (CHU Sainte-Justine, Montreal, Canada). A total of 352 participants were enrolled and 346 were randomized to either experimental (Buzzy device=172) or control (topical anesthetic=174) groups. For the participants allocated to the experimental, the Buzzy device was applied 5 cm above the insertion site group just before the needle-related procedure and was maintained in place throughout the procedure. For the participants allocated to the control group, a topical anesthetic cream (liposomal lidocaine 4%) was applied at the insertion site 30 minute before the needle-related procedure. Using an intention-to-treat analysis, the mean difference in procedural pain scores between the experimental group (3,92  3,13) and the control group (3,27  3,02) was 0.64 (95%CI -0,10 to 1,26) using the Color Analogue Scale, showing that the Buzzy device was not non-inferior to the topical anesthetic. Regarding the procedural distress, no significant difference was found between groups using the both measuring scales (Procedure Behavior Check List: p=0,104; Children’s Fear Scale: p=0,421). In addition, no significant difference was also found between groups regarding the success of the procedure at first attempt (p=0,489) and the memory for pain 24 hours after the procedure (p=0,346). Parents of both groups were satisfied with the received interventions (p=0,257) and the majority of nurses (65,0%) preferred the Buzzy device over the topical anesthetic. No adverse events occurred in the cold and vibrating group and one adverse event was reported in the topical anesthetic cream group. The non-inferiority of the cold and vibrating device over a topical anesthetic was not demonstrated for pain management of children during needle-related procedure in the ED. However, considering that topical anesthetics are underused in the ED setting, the Buzzy device seems to be a promising alternative as it is a rapid, low-cost, easy-to-use and reusable intervention. Consequently, it could be more likely to be translated into clinical practice and adopted by clinicians for routine use.