Clinical Studies In Children Research Articles

Prescribing Practices in Pediatrics and Drug Utilization Studies Promoting Pediatric Health

Knowledge of drug administration in children and infants lags behind that of adults for many reasons. These include developmental differences that affect the pharmacodynamic and pharmacokinetic profiles of drugs, ethical and financial reasons, research capabilities, and regulatory guidelines and constraints. Most of the drugs prescribed for children have not been tested in the pediatric population due to the difficulties in carrying out clinical studies in children and ethical issues due to children not being able to make their own decisions to participate in a clinical trial. Epidemiological evaluation of medicine use in elderly is now a highly visible topic, but drug prescribing studies in pediatric patients have been limited. The higher incidence of infections in pediatric population as compared to adults leads to higher prescription of Antimicrobial Drugs (AMDs), at times more than two in single prescription. The use of antibiotics in children has been a major area of concern. . Periodic prescriptions analysis and effective feedback to clinician should be done based on results to ensure rational prescribing and effective health care management, which will ultimately lead to a better child health. In this review article, we will to analyze prescribing practices in pediatrics and drug utilization studies promoting pediatric health.

DIPG-21. PRECLINICAL ASSESSMENT OF A MULTIMODAL TREATMENT APPROACH WITH GIVINOSTAT, PAXALISIB, AND RADIOTHERAPY FOR DIFFUSE MIDLINE GLIOMA (DMG)

Abstract BACKGROUND Despite an extensive body of clinical research conducted, the prognosis for patients with Diffuse Midline Glioma (DMG) has remained stagnant for the past five decades. Years of investigations underscore the robust resistance of DMG tumors to treatment, rendering monotherapy an improbable route to a cure. Recognizing the need for a multimodal approach, this study evaluated a treatment strategy incorporating radiotherapy and two brain-penetrable compounds with potential immunomodulatory effects, Givinostat and Paxalisib. METHODS We selected Givinostat, a pan-HDAC inhibitor undergoing clinical studies in children with Duchenne muscular dystrophy, by comprehensive screening of a panel of HDAC inhibitors for their efficacy in DMG neurosphere cultures, ability to penetrate the blood-brain barrier, and clinical utility. in addition, we selected the PI3K/mTOR inhibitor Paxalisib based on a phase II clinical trial currently undergoing in DMG patients (PNOC DMG Adaptive Combination Trial, PNOC022). The anti-tumor, radio-sensitizing, and immunomodulatory effects of both compounds were assessed in vitro and in immunocompetent mice, using various cytotoxicity and proteomic assays and (single-cell) sequencing techniques. RESULTS Our investigations revealed that the combination of Givinostat and Paxalisib exerts a profound cytostatic and cytotoxic effect on DMG cells, by reducing cell viability, enhancing DNA damage, and inducing apoptosis. Moreover, this combination therapy sensitized DMG cells to ionizing radiation, potentially by diminishing DNA repair mechanisms and elevating oxidative stress. Additionally, the combination of Givinostat and Paxalisib considerably reduced tumor growth in vivo and transformed the immune-cold microenvironment of DMG tumors into a pro-inflammatory phenotype. CONCLUSIONS This study positions Givinostat as a potential addition to the backbone of Paxalisib in forthcoming clinical trials, either as a radio/chemotherapy combination or as a foundation for immunotherapy.

Pharmacogenomics and non-genetic factors affecting drug response in autism spectrum disorder in Thai and other populations: current evidence and future implications.

Autism spectrum disorder (ASD) may affect family and social life profoundly. Although there is no selective pharmacotherapy for ASD, the Food and Drug Administration (FDA) has recommended risperidone/aripiprazole to treat the associated symptoms of ASD, such as agitation/irritability. Strong associations of some pharmacokinetic/pharmacodynamic gene variants, e.g., CYP2D6 and DRD2, with risperidone-induced hyperprolactinemia have been found in children with ASD, but such strong genetic associations have not been found directly for aripiprazole in ASD. In addition to pharmacogenomic (PGx) factors, drug-drug interactions (DDIs) and possibly cumulative effects of DDIs and PGx may affect the safety or effectiveness of risperidone/aripiprazole, which should be assessed in future clinical studies in children with ASD. Reimbursement, knowledge, and education of healthcare professionals are the key obstacles preventing the successful implementation of ASD pharmacogenomics into routine clinical practice. The preparation of national and international PGx-based dosing guidelines for risperidone/aripiprazole based on robust evidence may advance precision medicine for ASD.

Circulating autotaxin levels in healthy teenagers: Data from the Vitados cohort.

Autotaxin (ATX) is a secreted enzyme with a lysophospholipase D activity, mainly secreted by adipocytes and widely expressed. Its major function is to convert lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), an essential bioactive lipid involved in multiple cell processes. The ATX-LPA axis is increasingly studied because of its involvement in numerous pathological conditions, more specifically in inflammatory or neoplastic diseases, and in obesity. Circulating ATX levels gradually increase with the stage of some pathologies, such as liver fibrosis, thus making them a potentially interesting non-invasive marker for fibrosis estimation. Normal circulating levels of ATX have been established in healthy adults, but no data exist at the pediatric age. The aim of our study is to describe the physiological concentrations of circulating ATX levels in healthy teenagers through a secondary analysis of the VITADOS cohort. Our study included 38 teenagers of Caucasian origin (12 males, 26 females). Their median age was 13 years for males and 14 years for females, ranging from Tanner 1 to 5. BMI was at the 25th percentile for males and 54th percentile for females, and median blood pressure was normal. ATX median levels were 1,049 (450-2201) ng/ml. There was no difference in ATX levels between sexes in teenagers, which was in contrast to the male and female differences described in the adult population. ATX levels significantly decreased with age and pubertal status, reaching adult levels at the end of puberty. Our study also suggested positive correlations between ATX levels and blood pressure (BP), lipid metabolism, and bone biomarkers. However, except for LDL cholesterol, these factors were also significantly correlated with age, which might be a confounding factor. Still, a correlation between ATX and diastolic BP was described in obese adult patients. No correlation was found between ATX levels and inflammatory marker C-reactive protein (CRP), Body Mass Index (BMI), and biomarkers of phosphate/calcium metabolism. In conclusion, our study is the first to describe the decline in ATX levels with puberty and the physiological concentrations of ATX levels in healthy teenagers. It will be of utmost importance when performing clinical studies in children with chronic diseases to keep these kinetics in mind, as circulating ATX might become a non-invasive prognostic biomarker in pediatric chronic diseases.

Highly-sensitive chimerism analysis in blood after allogeneic hematopoietic cell transplantation in childhood leukemia: Results from the Nordic Microchimerism Study

Analysis of chimerism in blood post‐HCT using STR‐PCR is routinely applied in parallel with quantification of MRD to predict relapse of leukemia. Real time quantitative PCR (RQ-PCR) chimerism is 10‐ to 100‐fold more sensitive, but clinical studies in children are sparse. In a prospective multicenter study, we analyzed increasing mixed chimerism (IMC) in blood samples following transplantation for leukemia in 64 children. IMC was defined as a minimum increase of either 0.1% or 0.05% recipient DNA between two samples or a ≥10-fold increase. Samples closer than 30 days to diagnosis of relapse were omitted. The risk of relapse was higher in children with IMC of both 0.1% and 0.05% compared to children without IMC (27.8 (95% CI 4.4-175.8; P<.001), and 18.4 (95% CI 2.8-120.5; P=0.002), respectively). From the date of IMC, the 3-year CI of relapse or MRD-positivity was 26.7% (CI 9.4-47.0) and 18.5% (6.4-35.3) for IMC ≥ 0.1% (n=27) and ≥ 0.05% (n= 40), respectively. In the subset of children without an IMC ≥ 0.1% or ≥ 0.05%, CI of relapse or molecular relapse were 16.7% (5.0 -34.1) and 10.8% (3.4 -23.3), respectively. In all cases with a relapse undetectable by IMC, MRD remained undetectable prior to relapse and standard chimerism negative. In a landmark analysis, neither an IMC ≥ 0.1% nor ≥ 0.05% prior to 90 days post‐HCT was significantly associated with an increased relapse incidence. These results indicate that the serial monitoring of RQ‐PCR chimerism in peripheral blood post-HCT may be a valuable supplement to the minimal residual disease analysis for an early detection of relapse in acute childhood leukemia.

Review on Drug Evaluation Methods

The pharmacokinetics and pharmacodynamics of drugs are different in adult and paediatric populations, the latter being particularly heterogeneous. These differences in pharmacokinetics and pharmacodynamics justify specific studies but raise a number of ethical and practical issues. The main practical difficulties to circumvent while performing clinical studies in children are the invasiveness of the procedures and the obstacles to patient recruitment. The invasiveness related to pain/anxiety and blood loss precludes the performance of classical pharmacokinetic studies in children in many instances, particularly in neonates and infants. Population approaches, which rely on pharmacokinetic-pharmacodynamic modelling, are particularly appealing in paediatric populations because these models can cope with sparse data. The relevance of population approaches to investigation of the dose-concentration-effect relationships and to qualitative/quantitative assessment of factors that may explain interindividual variability has already been emphasized.

MODL-05 Metronomic Intrathecal Delivery of CDK4/6 Inhibitors in Preclinical Models of Pediatric Brain Tumors

INTRODUCTION: CDK4/6 inhibitors have shown promise against central nervous system (CNS) tumors in vitro. This class of drugs relies on long-term exposure. Their use in early phase clinical studies in children with CNS tumors has defined dose limitations due to systemic toxicity. We have sought to circumvent these limitations in using CDK4/6 inhibitors for pediatric CNS tumors by first demonstrating enhanced efficiency with long-term administration and exploiting prolonged intrathecal delivery (IT). METHODS: Pediatric CNS tumor cell lines were used for cell viability assays: ATRT (BT-12, BT-16), CPC (CCHE-45), diffuse midline glioma (DIPG-XIII, HSJD-007), and medulloblastoma (DAOY); the assays were conducted at 24h, 72h, and 7d post-administration of CDK4/6 inhibitors (abemaciclib, palbociclib, ribociclib). Half maximal growth inhibitory concentrations (GI50) and areas under the curve (AUC) were compared for short-term (24h, 72h) and long-term (7d) dose-response curves. Toxicity with chronic IT administration was assessed using a neurobehavioral safety profile of 7-day continuous infusion of 2.5mM palbociclib (n = 5) into the mouse lateral ventricle compared with vehicle (n = 4). RESULTS: Our results demonstrate increased CDK4/6 inhibitor potency with longer administration. The greatest reductions in short-term to long-term GI50 were observed in ATRT, CPC, and DIPG across all inhibitors. The most pronounced time-dependent efficacy was observed with palbociclib for ATRT and abemaciclib for CPC and DIPG. AUCs significantly decreased (P < 0.05) with increasing drug exposure time across all inhibitors. 7-day intraventricular palbociclib infusion was equivalent in safety to PBS at doses ranging from 1,000 to 10,000-fold the in vitro GI50. CONCLUSIONS: The efficiency of CDK4/6 inhibitors in pediatric CNS tumors is enhanced with prolonged exposure. Long-term IT administration can achieve high CNS doses without associated systemic toxicities. Translational efforts using a metronomic IT strategy are logical to explore for pediatric CNS tumors which have potential for a leptomeningeal disease pattern.

Emerging data on rifampicin pharmacokinetics and approaches to optimal dosing in children with tuberculosis

Introduction Despite its longstanding role in tuberculosis (TB) treatment, there continues to be emerging rifampicin research that has important implications for pediatric TB treatment and outstanding questions about its pharmacokinetics and optimal dose in children. Areas covered This review aims to summarize and discuss emerging data on the use of rifampicin for: 1) routine treatment of drug-susceptible TB; 2) special subpopulations such as children with malnutrition, HIV, or TB meningitis; 3) treatment shortening. We also highlight the implications of these new data for child-friendly rifampicin formulations and identify future research priorities. Expert opinion New data consistently show low rifampicin exposures across all pediatric populations with 10-20 mg/kg dosing. Although clinical outcomes in children are generally good, rifampicin dose optimization is needed, especially given a continued push to shorten treatment durations and for specific high-risk populations of children who have worse outcomes. A pooled analysis of existing data using applied pharmacometrics would answer many of the important questions remaining about rifampicin pharmacokinetics needed to optimize doses, especially in special populations. Targeted clinical studies in children with TB meningitis and treatment shortening with high-dose rifampicin are also priorities.

P385 Tailoring induction treatment for children with Crohn’s disease

Abstract Background Multiple clinical studies in children with Crohn’s disease (CD) have demonstrated the high efficacy of nutritional therapy with exclusive enteral nutrition (EEN) to induce remission and even to promote mucosal healing. However, EEN as inductive treatment may be not tolerated or inefficient and we are well aware of the paramount importance of a well conducted induction treatment for paediatric CD with the goal of an individualized induction treatment to improve the prognosis and the quality of life of inflammatory bowel disease (IBD) children. Methods A retrospective multicentre study including newly diagnosed children with CD treated with EEN as induction therapy was designed. The primary aim of the study was to study predictive factors of non- adherence to treatment. The secondary endpoint were predictive factors of clinical non-remission at the end of induction treatment. Those data together were analysed with the ultimate goal of trying to define an individualized induction treatment for children with CD. Results 376 CD children from, 14 IBD paediatric referral centres were enrolled in the study. The rate of EEN adherence was, 89 %. Colonic involvement and FC &amp;gt;, 600 μg/g at diagnosis were found associated with a reduced EEN adherence in univariate and multivariate analysis. The remission rate of those who completed induction treatment was, 67%. A multivariate analysis showed that factor determining lower remission rate were age &amp;gt;, 15 years and PCDAI &amp;gt;, 50. With those results we were able to create a decisional algorithm which is provided in figure 1. Conclusion EEN administered for, 8 weeks is effective for inducing clinical remission. The rate of adherence is high but there is a group of patients (colonic involvement + hight FC) which are at risk of non-adherence and thus may be candidate for alternative dietary induction regimens. Moreover, older patients with moderate to severe active disease (PCDAI&amp;gt;40), are at higher risk of failing clinical remission achievement after EEN and may benefit from an early anti-TNF alpha treatment. Personalized treatment strategies should be proposed weighing the benefits and risks based on each patient’s disease location, phenotype and disease activity with the overall aim of obtaining rapid control of inflammation to reduce long-term bowel damage.

Anesthetic Neurotoxicity in Children

The clinical pediatric anesthesiology community has been greatly affected by a growing body of research suggesting that sedative drugs and anesthetic agents may have long lasting detrimental neurocognitive effects in children. Various animal models have indicated apoptotic brain cell death and neurocognitive impairment following anesthetic exposure in early life. Although these studies cannot be directly extrapolated to anesthesia in children, parents and governmental regulatory agencies have been paying attention nonetheless. Adding to the evidence are a number of human epidemiologic studies that have documented neurologic deficits and cognitive decline following early anesthetic exposure. 1-4 Clinical studies in children exposed to general anesthesia have assessed outcome measures including academic performance or school readiness, validated neuropsychologic testing, and educational interventions for neurodevelopmental or behavioral problems.

General Anesthesia in the First 36 Months of Life.

Experimental data have shown that the developing brain is especially vulnerable to exogenous noxious substances. The potential effects of anesthetic drugs on brain growth and development are a matter of concern. Clinical studies of children who underwent general anesthesia in their earliest years can make a major contribution to our understanding of the effects of anesthetic drugs on infants and toddlers (i.e., children under age 5). Children born at term during the years 2007-2011 who were exposed to general anesthesia before their third birthday were included in the study. Data on general anesthesia were retrospectively evaluated, and the overall intelligence quotient (IQ) was determined prospectively as the primary target parameter. Children who had not been exposed to general anesthesia were recruited as a control group. The non-inferiority threshold was set at a difference of 5 IQ points out of a consideration of clinical relevance. 430 complete data sets were available from exposed children and 67 from members of the control group. The exposed group achieved a mean IQ score of 108.2, with a 95% confidence interval of [107; 109.4]; the corresponding values in the control group were 113 [110; 116.1]. Both groups achieved a mean score that was higher than the expected 100 points. After adjustment for age, socioeconomic status, and sex, the difference between the two groups was 2.9 points [0.2; 5.6], indicating a significantly better outcome in the control group than in the exposed group. The non-inferiority threshold of 5 IQ points was within the confidence interval; thus, non-inferiority was not demonstrated. The fact that both groups achieved a higher IQ score than the expected 100 points may be attributable, at least in part, to the restriction of the study to children born at term. The results indicate that general anesthesia in early childhood is not associated with markedly reduced intelligence in later years, although noninferiority could not be demonstrated.

The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma

Survival in high-risk pediatric neuroblastoma has remained around 50% for the last 20 years, with immunotherapies and targeted therapies having had minimal impact. Here, we identify the small molecule CX-5461 as selectively cytotoxic to high-risk neuroblastoma and synergistic with low picomolar concentrations of topoisomerase I inhibitors in improving survival in vivo in orthotopic patient-derived xenograft neuroblastoma mouse models. CX-5461 recently progressed through phase I clinical trial as a first-in-human inhibitor of RNA-POL I. However, we also use a comprehensive panel of in vitro and in vivo assays to demonstrate that CX-5461 has been mischaracterized and that its primary target at pharmacologically relevant concentrations, is in fact topoisomerase II beta (TOP2B), not RNA-POL I. This is important because existing clinically approved chemotherapeutics have well-documented off-target interactions with TOP2B, which have previously been shown to cause both therapy-induced leukemia and cardiotoxicity—often-fatal adverse events, which can emerge several years after treatment. Thus, while we show that combination therapies involving CX-5461 have promising anti-tumor activity in vivo in neuroblastoma, our identification of TOP2B as the primary target of CX-5461 indicates unexpected safety concerns that should be examined in ongoing phase II clinical trials in adult patients before pursuing clinical studies in children.

ЭНУРЕЗ КАК ОДИН ИЗ СИМПТОМОВ КОМОРБИДНЫХ СОСТОЯНИЙ У ДЕТЕЙ

Enuresis as an independent pathology in children over 5 years old occurs quite often, and amounts to 5–17% depending on the age. For a long time, the focus of research into this pathology has been on monosymptomatic enuresis, which is both a symptom and the main manifestation of the disease (nighttime urination incontinence). In-depth study into the problem of enuresis was initiated more than 20 years ago by prof. E.L. Vishnevsky in the Moscow City Center of Pathology of urination at the Speransky Children's City Clinical Hospital № 9. As a result of the work carried out jointly at several Russian centres in Moscow, Petrozavodsk, Sevastopol and Anadyr by children’s urologists, neurologists, nephrologists and paediatricians, a conclusion was reached on encuresis as a manifestation of comorbid conditions. The article presents the results of of the clinical studies in children with attention-deficit/hyperactivity disorder (ADHD), overactive bladder (OAB), metabolic nephropathies, and other somatic pathologies in which enuresis was a manifested clinical syndrome. Differential diagnosis and effective treatment tactics in such cases require more thorough research using clinical, neurophysiological and instrumental methods, which makes it possible to establish a diagnosis in a timely manner and administer an adequate therapy.

Botulinum Toxin A and Osteosarcopenia in Experimental Animals: A Scoping Review.

We conducted a scoping review to investigate the effects of intramuscular injection of Botulinum Toxin A (BoNT-A) on bone morphology. We investigated if the muscle atrophy associated with Injection of BoNT-A had effects on the neighboring bone. We used the search terms: osteopenia, bone atrophy, Botulinum Toxin A, Micro-CT, mice or rat. The following databases were searched: Medline, Embase, PubMed and the Cochrane Library, between 1990 and 2020. After removal of duplicates, 228 abstracts were identified of which 49 studies satisfied our inclusion and exclusion criteria. The majority of studies (41/49) reported a quantitative reduction in at least one measure of bone architecture based on Micro-CT. The reduction in the ratio of bone volume to tissue volume varied from 11% to 81% (mean 43%) according to the experimental set up and study time points. While longer term studies showed muscle recovery, no study showed complete recovery of all bone properties at the termination of the study. In experimental animals, intramuscular injection of BoNT-A resulted in acute muscle atrophy and acute degradation of the neighboring bone segment. These findings may have implications for clinical protocols in the use of Botulinum Toxin in children with cerebral palsy, with restraint recommended in injection protocols and consideration for monitoring bone density. Clinical studies in children with cerebral palsy receiving injections of Botulinum are indicated.

Nutritional Therapy Strategies in Pediatric Crohn's Disease.

The increase in incidences of pediatric Crohn’s Disease (CD) worldwide has been strongly linked with dietary shifts towards a Westernized diet, ultimately leading to altered gut microbiota and disturbance in intestinal immunity and the metabolome. Multiple clinical studies in children with CD have demonstrated the high efficacy of nutritional therapy with exclusive enteral nutrition (EEN) to induce remission with an excellent safety profile. However, EEN is poorly tolerated, limiting its compliance and clinical application. This has spiked an interest in the development of alternative and better-tolerated nutritional therapy strategies. Several nutritional therapies have now been designed not only to treat the nutritional deficiencies seen in children with active CD but also to correct dysbiosis and reduce intestinal inflammation. In this review, we report the most recent insights regarding nutritional strategies in children with active CD: EEN, partial enteral nutrition (PEN), Crohn’s disease exclusion diet (CDED), and CD treatment-with-eating diet (CD-TREAT). We describe their setup, efficacy, safety, and (dis)advantages as well as some of their potential mechanisms of action and perspectives. A better understanding of different nutritional therapeutic options and their mechanisms will yield better and safer management strategies for children with CD and may address the barriers and limitations of current strategies in children.

Anesthetic Neurotoxicity in Children

The clinical pediatric anesthesiology community has been greatly affected by a growing body of research suggesting that sedative drugs and anesthetic agents may have long lasting detrimental neurocognitive effects in children. Various animal models have indicated apoptotic brain cell death and neurocognitive impairment following anesthetic exposure in early life. Although these studies cannot be directly extrapolated to anesthesia in children, parents and governmental regulatory agencies have been paying attention nonetheless. Adding to the evidence are a number of human epidemiologic studies that have documented neurologic deficits and cognitive decline following early anesthetic exposure. 1-4 Clinical studies in children exposed to general anesthesia have assessed outcome measures including academic performance or school readiness, validated neuropsychologic testing, and educational interventions for neurodevelopmental or behavioral problems.

SUN-098 Low-Dose Infigratinib Treatment Does Not Lead to Changes in Phosphorous Preclinically in Mice

BACKGROUND: Infigratinib (BGJ398) is a potent and selective FGFR1-3 inhibitor under evaluation for the treatment of achondroplasia, the most common form of disproportionate short stature. Low doses of infigratinib were shown to be effective in improving skeletal abnormalities in a mouse model of achondroplasia [Demuynck et al. 2019; Komla-Ebri et al. 2016]. At higher doses in adult patients (e.g. 10-100-fold the dose shown to have efficacy in preclinical models of achondroplasia) infigratinib appears to be associated with elevation in phosphorus, an effect known to be associated with FGFR1 inhibition. Specifically, FGFR1 inhibition leads to decreases in FGF23, which, in turn, leads to decreased excretion of phosphate by the kidneys. We sought to understand the relationship between lower doses of infigratinib and changes in phosphorus in preclinical animal models. Methods: Changes in phosphorus were tested at multiple doses in three different species - mouse, rat, and dog - across five different studies. Infigratinib was given orally at doses ranging from 0.03 mg/kg to 30 mg/kg. Both PK and PD (i.e., phosphorus) data was available in all species. Measurement days ranged from day 10 to week 12, although PK/PD measurements occurred within 1 day of each other. All animals were treated in accordance with AVMA guidelines. Results: No significant dose-phosphorus relationship was observed in rats and mice treated with doses of infigratinib ranging from 0.03 mg/kg to 5 mg/kg. A dose-phosphorus and exposure (AUC0-24)-phosphorus relationship was observed at doses of infigratinib ≥10 mg/kg across transgenic mouse, rat, and dog studies. At low doses, the exposure (AUC0-24)-phosphorus relationship showed a shallow slope with linear regression analysis in rats and mice. Conclusions: These findings from five studies in three different species indicate that the exposure-phosphorus relationship is consistent. Importantly, no relationship was observed between dose and phosphorus levels in rats and mice treated with infigratinib at or below 5 mg/kg. Despite the fact that infigratinib is a FGFR1, 2 and 3 inhibitor, low doses of infigratinib shown previously to exert a significant effect in improving skeletal abnormalities in an achondroplasia mouse model, do not seem to result in meaningful changes in phosphorus. These experiments demonstrate that at doses of infigratinib much lower than used in oncology - like those being considered for use in clinical studies of achondroplasia - infigratinib is less likely to cause hyperphosphatemia. Infigratinib will be evaluated in global clinical studies in children with achondroplasia in 2020.

Efficacy of cannabinoids in pharmacoresistant epilepsy: A narrative review of the literature

Epilepsy is a common neurological disorder that affects approximately 1% of the world’s pop7ulation. About one third of those patients suffer from treatment-resistant epilepsy (TRE8), defined as failure to stop seizures despite adequate trials of at least two medications at therapeutic dosages. There has been a growing interest in the development of novel antiepileptic drugs with different mechanisms of action. This narrative review, based on 42 references retrieved from Scopus and Medline, discusses the scientific data from human and animal studies regarding the efficacy of cannabis-based treatment for epilepsy. Benefits have been described in pre-clinical and clinical studies in children, but ongoing research will clarify the real role of cannabinoids in TRE.

The first study in pediatric: Population pharmacokinetics of sirolimus and its application in Chinese children with immune cytopenia.

The narrow therapeutic index and large inter-individual variability in sirolimus pharmacokinetics (PK) make therapeutic drug monitoring (TDM) necessary. Factors responsible for PK variability are not well understood, and published PK studies do not include pediatric patients with immune cytopenia. The objective of this study was to characterize the PK of sirolimus in pediatric patients with immune cytopenia and to develop a population PK model in Chinese children and evaluate its utility for dose individualization. A total of 27 children with either acquired or congenital immune cytopenia aged 8.16 ± 3.60 years (range: 1–15 years) were included. TDM data for sirolimus were collected. The population PK model of sirolimus was described using the nonlinear mixed-effects modeling (Phoenix NLME 1.3 software) approach. Covariate analysis was applied to select candidate factors associated with PK parameters. The final model was validated using bootstrap (1000 runs) and visual predictive check (VPC) method. A one-compartment model with first-order absorption and elimination was developed. The outcome parameters were as follows: apparent clearance (CL/F) 5.63 L/h, apparent distribution volume (V/F) 144.16 L. Inter-individual variabilities for CL/F and V/F were 3.53% and 7.27%, respectively. The intra-individual variability of proportional error model was 22.45%. The covariate test found that body weight and total bilirubin were strongly associated with clearance; however, we did not find the relevance between the covariate and volume of distribution of sirolimus. Personalized dosage regimens were provided based on Bayesian method. The oral dose should be adjusted according to weight and total bilirubin. This is the first study to describe a population PK model of sirolimusin pediatric patients with immune cytopenia. Population pharmacokinetic (PPK) model–based dose individualization of sirolimus and the design of future clinical studies in children will be facilitated by the developed model in this study.

Étude de l’anxiété-trait et l’anxiété-état chez les enfants anémiques : région de Chefchaouen au nord du Maroc

Anemia can contribute to the deterioration of quality of life and have a significant physical impact leading to an increase in morbidity, but its psychological impact remains underestimated and is not well clarified, especially in school-age children. Our objective was to assess the level of anxiety in a group of anemic children and compare it to a group of children with normal hemoglobin. Our population consisted of 170 students aged between 8 and 14 years old, including 51 anemic and 119 with normal hemoglobin. Anxiety is assessed using Spielberger's STAI anxiety inventory scale, according to its two concepts: state and trait. Our results show a median hemoglobin of 10,7 [9,9,9,10] in anemic students and 14,3 [2–13,13–15] in non-anemic students (P=0,000). The mean state and trait anxiety scores are respectively 31,88±7,25 and 34,82±6,84 in anemic students and 2,55±6,37 and 34,89±5,7 in not anemic, without significant difference between the two groups. In conclusion, our study did not report high levels of anxiety in anemic children; the means are comparable to those found in clinical studies in children of similar age.