Pauline De Bruyne

Challenging factors for enuresis treatment: Psychological problems and non-adherence

The evidence for organic pathogenetic factors in enuresis and the discovery of effective therapies targeting the bladder and/or nocturnal diuresis have overwhelmed every potential role of psychological factors in pathogenesis and treatment. However, psychopathology is still important in enuresis because according to the document of the International Childrens Continence Society (ICCS) 20-30% of the children with enuresis have at least one psychological/psychiatric disorder at rates two times higher than non-wetting children. The most common comorbid disorder with enuresis is attention deficit hyperactivity disorder. The aim of this review is to translate the existing evidence on the importance of a psychological screening into daily clinical practice of the medical practitioner. The use of the minimal psychological screening tool should be considered mandatory in each primary setting. If psychological problems are indicated, referral of the patient to a multidisciplinary setting should be considered, not only to allow psychological assessment to screen for a possible psychopathology, but also since therapy resistance might be expected. This review concentrates on two items from psychopathology/psychotherapy that might predict insufficient treatment response: the psychological comorbidities as described according to the DSM-5 criteria and the underestimated importance of therapy adherence. Adherence is a cornerstone of effective therapy in enuresis. It is a problem involving the doctor, the patient, and the parents. Increasing adherence takes effort and is time-consuming. But it is worthwhile knowing that several studies have demonstrated that high adherence is associated with high therapy success of enuresis. Eventually, this is the ultimate goal of treatment.

Changes in prescription patterns of acid-suppressant medications by Belgian pediatricians: analysis of the national database, [1997-2009].

Objective: The aim of this study was to examine the trend in the prescribing of proton pump inhibitors (PPIs) and histamine 2-receptor antagonists (H2-RAs) for children in Belgium from 1997 to 2009 to encourage discussion regarding appropriate clinical use. Methods: Monthly claim–based data for PPIs and H2-RAs were obtained from the national health insurance database (Pharmanet 1997–2009). Results: The total monthly volume of all reimbursed antireflux medications, prescribed by Belgian pediatricians, increased 7-fold from 20,782 daily defined doses (DDDs) in January 1997 to 142,912 DDDs in June 2009. During this study period, reimbursed volume of H2-RAs increased from 2575 to 38,996 DDDs and of PPIs from 3472 to 103,926 DDDs per month. Conclusions: PPI use has increased substantially in children. Its use does not seem to be commensurate with the prevalence of gastroesophageal reflux disease in children. This study encourages clinical discussion regarding well-considered use of these drugs in children.

The Potential Use of Piglets as Human Pediatric Surrogate for Preclinical Pharmacokinetic and Pharmacodynamic Drug Testing

Pediatric drug research is still substandard, not reaching the same quality level as adult drug research. Despite the efforts made by the Food and Drug Administration and European Medicines Agency to reduce off-label use in children, the lack of clinical studies involving the pediatric population still stands. Pharmacokinetic and pharmacodynamics studies (PK/PD) taking growth and maturation into account are necessary to rationalize dosing strategies in children. Currently, traditional animal models such as rats, mice, dogs and primates are used to conduct pharmacokinetic and pharmacodynamic studies, however age-related trials are rather uncommon. Moreover, these species have several shortcomings as animal models, such as a different physiology and anatomy of the gastrointestinal tract in dogs or the ethical aspects for the use of primates. In contrast, piglets might be potential biomedical pediatric animal models because of the good resemblance with humans, anatomically, physiologically and biochemically. This review summarizes the comparative anatomy and physiology and postnatal development of piglets and infants, focusing on six major topics, namely growth, cardiovascular system, gastrointestinal tract, liver, kidney and integument. Furthermore, the application of piglets as animal model in pediatric PK/PD research is discussed.

Are antihistamines effective in children? A review of the evidence

Background and aims During the last decades, much attention has been paid to off-label and unlicensed prescriptions in paediatrics. However, on-label prescribing can also cause health issues. In this paper, the case of first-generation H1-antihistamines is investigated, notably the range of indications for which products are licensed in different European countries and the evidence base (or lack thereof) for each indication, as well as reported adverse drug reactions. Methods Review of the Summary of Product Characteristics of first-generation H1-antihistamines with a focus on paediatric use. This is plotted against the evidence available in the literature. Results This investigation shows a large variability in labelled indications and licensing ages when compared in five different European countries. Moreover, most of the indications are not based on clinical trials evaluating efficacy and safety of these drugs in children. Conclusions Many of the licensed indications of first-generation antihistamines do not appear to be evidence based.

Systemic fluoroquinolone prescriptions for hospitalized children in Belgium, results of a multicenter retrospective drug utilization study

BackgroundFluoroquinolones (FQ) are increasingly prescribed for children, despite being labeled for only a limited number of labeled pediatric indications. In this multicenter retrospective drug utilization study, we analyzed indications for systemic FQ prescriptions in hospitalized children and the appropriateness of the prescribed dose.MethodsUsing data obtained from electronic medical files, the study included all children who received a systemic FQ prescription in two Belgian university children’s hospitals between 2010 and 2013. Two authors reviewed prescribed daily doses. Univariate and multivariate logistic regression models were used to analyze risk factors for inadequately dosing.Results262 FQ prescriptions for individual patients were included for analysis. 16.8% of these prescriptions were for labeled indications, and 35.1% were guided by bacteriological findings. Prescribed daily dose was considered to be inappropriate in 79 prescriptions (30.2%). Other FQ than ciprofloxacin accounted for 9 prescriptions (3.4%), of which 8 were correctly dosed. Underdosing represented 45 (56.9%) dosing errors. Infants and preschool children were at particular risk for dosing errors, with associated adjusted OR of 0.263 (0.097–0.701) and 0.254 (0.106–0.588) respectively.ConclusionsFQ were often prescribed off-label and not guided by bacteriological findings in our study population. Dosing errors were common, particularly in infants and preschool children. FQ prescriptions for children should be improved by specific pediatric antimicrobial stewardship teams. Furthermore, pharmacokinetic studies should optimise dosing recommendations for children.

Toxicity of long-term use of proton pump inhibitors in children

Proton pump inhibitor (PPI) use is becoming increasingly common. Although the toxicity profiles of PPIs are not well understood particularly in children, PPIs have been associated with increased risks of gastrointestinal and respiratory tract infection, vitamin B12 deficiency, hypomagnesaemia, bone fractures, and rebound hyperacidity after discontinuation. Prescribers should take into account that PPI uses pose toxicity risks, which remain to be fully characterised in infants and children.

Therapeutic efficacy and safety of ACE inhibitors in the hypertensive paediatric population: a review

Purpose Since 1997, strong incentives have been introduced worldwide to improve access to safe and effective medicines addressing the therapeutic needs of children. ACE inhibitors, the most prescribed antihypertensive drugs in the paediatric population, are one of the prototype drugs targeted by the legislation initiatives. Our purpose in assembling this review is to evaluate and describe the current evidence for the efficacy and safety profile of ACE inhibitors in the paediatric population. Methods The authors made a descriptive review of the literature from 1980 to 2015 using the following search terms: hypertension, child, paediatric, ACE (inhibitors), renin–angiotensin aldosterone system, captopril, lisinopril, enalapril, ramipril and fosinopril. Results A total of 16 studies evaluating efficacy and safety of ACE inhibitors were included in this review. The included studies demonstrate that ACE inhibitors have the potency to decrease the systolic and/or diastolic blood pressure with an overall favourable safety profile in a short-term period. More importantly, the incentives resulted in an improvement of the overall availability of paediatric labelling, dosing and safety information for ACE inhibitors. However, they failed to fulfil several of paediatric needs: absence of long-term safety data on growth and maturation, absence of commercially available child-friendly formulations and incomplete evaluation of the entire paediatric hypertension population. Conclusion Additional efforts are needed to close the gap between the availability of drugs that are labelled and indicated for paediatric use and the actual drug usage in children, especially in young children, neonates and children with severe hypertension, renal transplantation or severe renal impairment.

Confirmation of an ARID2 defect in SWI/SNF-related intellectual disability

We present a 4‐year‐old girl with delayed neuromotor development, short stature of prenatal onset, and specific behavioral and craniofacial features harboring an intragenic deletion in the ARID2 gene. The phenotype confirmed the major features of the recently described ARID2‐related intellectual disability syndrome. However, our patient showed overlapping features with Nicolaides‐Baraitser syndrome and Coffin‐Siris syndrome, providing further arguments to reclassify these disorders as “SWI/SNF‐related intellectual disability syndromes.”

Population Pharmacokinetic Modeling of a Desmopressin Oral Lyophilisate in Growing Piglets as a Model for the Pediatric Population

Desmopressin is used to treat primary nocturnal enuresis in children. Over the years, various formulations of desmopressin were commercialized of which the sublingual melt tablet is preferred in the pediatric population, despite the lack of full PK studies in this population. A full PK study was performed in growing conventional piglets to evaluate if this juvenile animal model can provide supplementary information to complement the information gap in the pediatric population. A desmopressin sublingual melt tablet (120 μg) was administered to 32 male piglets aged 8 days, 4 weeks, 7 weeks, and 6 months (each group n = 8). Population PK (pop-PK) analysis was performed to derive the PK parameters, the between- and within-subject variabilities and the effects of covariates. Desmopressin demonstrated two-compartmental PK, with a dual, sequential absorption process, and linear elimination. Body weight was the only significant covariate on clearance and on apparent volume of distribution of the central compartment. In human pediatric trials, no double peak in the absorption phase was observed in the plasma concentration-time curves, possibly due to the sparse sampling strategy applied in those pediatric studies. Therefore, it is recommended to perform additional studies, based on the sampling protocol applied in the current study.

Ethical considerations of researchers conducting pediatric clinical drug trials: a qualitative survey in two Belgian university children’s hospitals

There is a general consensus about the underlying theoretical ethical principles that ground the practice of pediatric clinical trials: scientific necessity, good risk/benefit ratio, minimized burden, and parental consent/child assent. However, these principles are so broadly construed that it is not always clear how they should be applied in clinical practice. We conducted a qualitative study at Ghent University Hospital and the hospital of the Dutch-speaking university of Brussels on how researchers weigh ethical principles, assess the risk/benefit balance, estimate patient experience, and experience informed consent procedures in pediatric drug studies. Based on our assessment of the burden and risk versus benefit ratio in 62 pediatric drug research protocols, we selected 21 studies for further study to maximize diversity. Twenty-seven researchers (17 physicians, 10 study nurses) completed a qualitative survey about their study. We compared their responses to our assessments. The risk benefit assessment of our participants about their own research projects resembled our assessment almost perfectly. Assessing burden appeared to be more subjective. The researchers were confident in their ability to obtain valid consent. However, we question whether this confidence is warranted.Conclusion: We argue for constant ethical reflexivity in pediatric clinical trials, because broad ethical principles are not always easy to apply to specific situations.What is Known:• Several international guidelines and a large body of scientific literature indicate a broad consensus about the basic ethical framework for pediatric clinical trials, based on risk benefit assessment and respect for autonomy.• Little is known about how researchers implement these broad principles in practice.What is New:• Researchers’ risk/benefit assessments about their own studies resembled the assessment of neutral peers, assessing burden was more subjective.• Researchers were very confident in their ability to obtain valid informed consent.