Removing barriers to accessing medical cannabis for paediatric patients.

Medical cannabis (MC) may offer therapeutic benefits for children with complex neurological conditions and chronic diseases. In Canada, parents, and caregivers frequently report encountering barriers when accessing MC for their children. These include negative preconceived notions about risks and benefits, challenges connecting with a knowledgeable healthcare provider (HCP), the high cost of MC products, and navigating MC product shortages. In this manuscript, we explore several of these barriers and provide recommendations to decision-makers to enable a family-centered and evidence-based approach to MC medicine and research for children.

Gene-based drug therapy in children.

The past two decades have seen enormous advancements in medical knowledge around the role of genetic factors of variability, both in human disease and drug response. This knowledge is increasingly being translated into guidelines that inform drug dosing, monitoring for efficacy and safety, and determining the suitability of specific agents to treat patients. Health Canada and the U.S. Food and Drug Administration have recommended using genetic information to guide dosing for more than 20 drugs. There are no current, comprehensive paediatric guidelines to assist health care professionals in the use of genetics to inform medication dosing, safety, and efficacy in children, and such guidance is urgently needed. This statement helps to guide clinician understanding of the role of pharmacogenetics and how to use this information when prescribing medications in paediatrics.

La pharmacothérapie en fonction des gènes.

Depuis vingt ans, le savoir médical sur le rôle des facteurs génétiques de variabilité a énormément évolué, tant à l'égard des maladies humaines que de la réponse aux médicaments. Ce savoir se traduit de plus en plus par des directives qui influent sur la posologie, la surveillance de l'efficacité et de l'innocuité et la détermination de la pertinence d'agents particuliers pour traiter les patients. Santé Canada et la Food and Drug Administration des États-Unis recommandent d'utiliser l'information génétique pour orienter la posologie de plus de 20 médicaments. Il n'existe actuellement pas de directives pédiatriques complètes pour aider les professionnels de la santé à utiliser la génétique afin d'établir la posologie, l'innocuité et l'efficacité des médicaments chez les enfants, et ces directives s'imposent d'urgence. Le présent document de principes aide le clinicien à comprendre le rôle de la pharmacogénétique et à utiliser l'information qu'il en tire pour prescrire des médicaments en pédiatrie.

Beta-lactam allergy in the paediatric population.

Beta-lactam allergy is commonly diagnosed in paediatric patients, but over 90% of individuals reporting this allergy are able to tolerate the medications prescribed after evaluation by an allergist. Beta-lactam allergy labels are associated with negative clinical and administrative outcomes, including use of less desirable alternative antibiotics, longer hospitalizations, increasing antibiotic-resistant infections, and greater medical costs. Also, children with true IgE-mediated allergy to penicillin medications are often advised to avoid all beta-lactam antibiotics, including cephalosporins, which is likely unnecessary in greater than 97% of those reporting penicillin allergies. Most patients can be safely treated with penicillin or amoxicillin if they do not have a history compatible with IgE-mediated or systemic, delayed reactions such as Stevens-Johnson syndrome (SJS), serum sickness-like reactions, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, or acute generalized exanthematous pustulosis (AGEP). Guidance is provided on how to stratify risk of beta-lactam allergy, and on test dosing and monitoring in the outpatient setting for patients deemed low risk. Guidance for patients at higher risk of beta-lactam allergy includes criteria for appropriate referral to allergists and the use of alternative antimicrobials, such as cephalosporins, while awaiting specialist assessment.

Innovative approaches to investigator-initiated, multicentre paediatric clinical trials in Canada.

Data from clinical trials are needed to guide the safe and effective use of medicines in children. Clinical trials are challenging to design and implement in all populations, and children present additional considerations. Several regions including the UK, USA and Europe have established clinical trial infrastructure to capitalise on expertise and promote clinical trials enrolling children. Our objective is to describe the partnerships and operational considerations for the development of paediatric clinical trials infrastructure in Canada. We describe the design and conduct of four emergency room paediatric trials, with four separate sponsors, across four provinces in parallel. Operations discussed include multisite contract development, centralised risk-based data monitoring, ethical review and patient engagement. We conclude with lessons learnt, additional challenges and potential solutions to facilitate drug development for children in Canada.

Anti-Saccharomyces cerevisiae Antibodies as a Prognostic Biomarker in Children With Crohn Disease.

OBJECTIVE: Although anti-Saccharomyces cerevisiae antibodies (ASCAs) could be a useful biomarker in differentiating Crohn disease (CD) from ulcerative colitis (UC), their role as prognostic markers in children with CD has been underinvestigated. This longitudinal prospective observational study aimed to assess the prognostic value of ASCA status among children with CD managed using biologics. METHODS: The study population comprised children with inflammatory bowel disease diagnosed with CD from 2012 to 2018. Cox regression model with adjustment for a priori covariates was used to examine the response to anti-tumor necrosis factor (TNF) biological therapy among ASCA-positive patients in comparison to ASCA-negative patients. RESULTS: There were 273 measurements available from the study cohort comprising children with CD, who were followed up for a median duration of 14 months (interquartile range 5-42). ASCA-positive patients had a higher risk for moderate to severe clinical disease (odds ratio 2.88; 95% confidence interval [CI] 1.2-7.55) and extensive endoscopic distribution (odds ratio 3.30; CI 1.12-9.74) at baseline in comparison to ASCA-negative patients, respectively. In comparison to ASCA immunoglobulin G (IgG)-negative patients, ASCA IgG-positive patients who were treated with biologics had a significantly lower relapse rate (adjusted hazard ratio 0.12; CI 0.02-0.93). Ten (14%) patients had an unstable ASCA value with either ASCA immunoglobulin A or ASCA IgG status changing from positive to negative or vice versa. CONCLUSIONS: ASCA-positive children with CD present with more extensive (endoscopic) and clinically severe disease. ASCA IgG is a useful prognostic marker among children with CD who receive biologics.

Review of thiamine deficiency disorders: Wernicke encephalopathy and Korsakoff psychosis.

Wernicke encephalopathy (WE) and Korsakoff psychosis (KP), together termed Wernicke-Korsakoff syndrome (WKS), are distinct yet overlapping neuropsychiatric disorders associated with thiamine deficiency. Thiamine pyrophosphate, the biologically active form of thiamine, is essential for multiple biochemical pathways involved in carbohydrate utilization. Both genetic susceptibilities and acquired deficiencies as a result of alcoholic and non-alcoholic factors are associated with thiamine deficiency or its impaired utilization. WKS is underdiagnosed because of the inconsistent clinical presentation and overlapping of symptoms with other neurological conditions. The identification and individualized treatment of WE based on the etiology is vital to prevent the development of the amnestic state associated with KP in genetically predisposed individuals. Through this review, we bring together the existing data from animal and human models to expound the etiopathogenesis, diagnosis, and therapeutic interventions for WE and KP.

Prenatal antibiotic exposure and childhood asthma: a population-based study.

Antibiotic use during infancy alters gut microbiota and immune development and is associated with an increased risk of childhood asthma. The impact of prenatal antibiotic exposure is unclear. We sought to characterise the association between prenatal antibiotic exposure and childhood asthma.We performed a population-based cohort study using prescription records, hospitalisation records and physician billing claims from 213 661 mother-child dyads born in Manitoba, Canada between 1996 and 2012. Associations were determined using Cox regression, adjusting for maternal asthma, postnatal antibiotics and other potential confounders. Sensitivity analyses evaluated maternal antibiotic use before and after pregnancy.36.8% of children were exposed prenatally to antibiotics and 10.1% developed asthma. Prenatal antibiotic exposure was associated with an increased risk of asthma (adjusted hazard ratio (aHR) 1.23, 95% CI 1.20-1.27). There was an apparent dose response (aHR 1.15, 95% CI 1.11-1.18 for one course; aHR 1.26, 95% CI 1.21-1.32 for two courses; and aHR 1.51, 95% CI 1.44-1.59 for three or more courses). Maternal antibiotic use during 9 months before pregnancy (aHR 1.27, 95% CI 1.24-1.31) and 9 months postpartum (aHR 1.32, 95% CI 1.28-1.36) were similarly associated with asthma.Prenatal antibiotic exposure was associated with a dose-dependent increase in asthma risk. However, similar associations were observed for maternal antibiotic use before and after pregnancy, suggesting the association is either not directly causal, or not specific to pregnancy.

Randomized controlled trials in pediatric patients had higher completion rates than adult trials: a cross-sectional study.

OBJECTIVE: Conduct of clinical trials is perceived to be more challenging in children than in adults. This study aimed to evaluate the impact of the age of participants on completion rates of randomized controlled trials (RCTs). STUDY DESIGN AND SETTING: A cross-sectional study on RCTs registered in the ClinicalTrials.gov database. All RCTs registered up to December 31, 2016, were extracted and were classified according to their recruitment status: active, completed, or discontinued and according to the age of participants: children (<17 years), adults (≥18 years), and mixed-age population. A logistic regression model was applied to assess the impact of participant's age category on trial completion while controlling for other relevant trial features. RESULTS: A total of 65,095 registered RCTs were identified. Among pediatric trials, 49.9% were completed and 8.5% were discontinued. Among adult and mixed age RCTs, respectively, 49.7% and 47.9% were completed whereas, 10.2% and 9.4% were discontinued. Overall, pediatric and mixed age RCTs were more likely to be registered as completed than adult RCTs (odds ratio: 1.16, 95% CI: 1.02-1.30; odds ratio: 1.15, 95% CI: 1.04-1.27, respectively). Also, funding source, type of intervention under evaluation, primary trial purpose, use of a blinding procedure, use of a placebo, and participants' assignment model were identified as independent predictors of RCT completion. CONCLUSION: Contrary to current perceptions and despite several specific challenges, recruitment of children and adolescents is not a limiting factor to completing a RCT. Other study features such as funding source, impact completeness and should be carefully considered before initiating research.

Antibiotic-Induced Liver Injury in Paediatric Outpatients: A Case-Control Study in Primary Care Databases.

INTRODUCTION: Antibiotics are the most commonly prescribed drug class in children. Real-world data mining on the paediatric population showed potential associations between antibiotic use and acute liver injury. OBJECTIVE: We assessed risk estimates of liver injury associated with antibiotic use in children and adolescent outpatients. METHODS: A large, multi-database, population-based, case-control study was performed in people <18 years of age from two European countries (Italy and The Netherlands) during the period 2000-2008. All potential cases of liver injury were automatically extracted from three databases and then manually validated based on Council for International Organizations of Medical Sciences (CIOMS) criteria and by exclusion of all competing causes for liver injury. Up to 100 control participants were sampled for each case and were matched on index date of the event, age, sex and database. Based on prescription data, antibiotic exposure was categorized as current, recent or past use by calculating the time period between the end of prescription and the index date. Multivariate conditional logistic regression analyses were applied to calculate odds ratios (ORs) as a measure of the association (with 95% confidence interval [CI]). RESULTS: We identified 938 cases of liver injury and matched to 93,665 controls. Current use of overall antibiotics is associated with a threefold increased risk of liver injury compared with past use (adjusted OR [ORadj] 3.22, 95% CI 2.57-4.03). With regard to individual antibiotics, the risk is significantly increased for current use of each antibiotic (p < 0.005), except for azithromycin. Risk estimates vary from the lowest ORadj of 1.86 (95% CI 1.08-3.21) for amoxicillin to the highest ORadj of 24.16 (95% CI 11.78-49.54) for cotrimoxazole (i.e. sulphamethoxazole/trimethoprim) and 26.70 (95% CI 12.09-58.96) for ceftriaxone. Sensitivity analyses confirm the associations for ceftriaxone, cotrimoxazole, and clarithromycin. CONCLUSION: Antibiotic-induced liver injury in children is heterogeneous across the use of individual antibiotics. When prescribing ceftriaxone, cotrimoxazole and clarithromycin in children, paediatricians should definitely be aware of their potential risk of liver injury, even if for short periods.

Proposed trial: safety and efficacy of resveratrol for the treatment of non-alcoholic fatty liver disease (NAFLD) and associated insulin resistance in adolescents who are overweight or obese adolescents - rationale and protocol.

Non-alcoholic fatty liver (NAFL) disease (NAFLD) affects 30% of overweight adolescents and increases the risk of type 2 diabetes mellitus (T2D). Resveratrol is a naturally occurring compound with potential to reverse NAFL and its associated insulin resistance in adults. The use of resveratrol to reduce risk for T2D through its effect on NAFL has not been examined to date in youth. This paper provides a literature review and protocol for a 30 day proof of principle trial of resveratrol in a population of adolescents at risk for T2D. This randomized double-blind controlled trial is designed with the primary objective of evaluating a twice daily supplementation of 75 mg of resveratrol for safety and tolerability in overweight and obese adolescent subjects (13 to <18 years of age) with NAFL. Secondary objectives are to determine the effect size of the intervention on hepatic steatosis and whole body insulin sensitivity. Adolescents in the intervention arm (n = 10) will receive oral supplementation of resveratrol 75 mg twice daily (with breakfast and dinner) for a total daily dose of 150 mg for the duration of 30 days. The comparison group (n = 10) will receive a placebo twice daily for 30 days. Both cases and controls will receive a standardized lifestyle intervention program. Subjects in both groups will be followed for an additional 30 days post intervention for total study duration of approximately 60 days. Primary outcome measures include a primary side effect profile determined by participant interview, a side effect profile determined by serum biochemistry and vital signs. Secondary outcome measures include an oral glucose tolerance test, liver and cardiac fat content measured by magnetic resonance spectroscopy, anthropometric measures of overweight/obesity, inflammatory markers, and cardiac function and morphology measured with ultrasonography. Additional outcome measures include serum concentrations of resveratrol, compliance to protocol, physical activity, and nutritional assessment. This study will determine the safety and tolerability of resveratrol in an overweight adolescent population and inform the design of a larger randomized controlled trial.

Time-trends in the prescribing of gastroprotective agents to primary care patients initiating low-dose aspirin or non-steroidal anti-inflammatory drugs: a population-based cohort study.

AIMS: Low-dose aspirin (LDA) and non-steroidal-anti-inflammatory drugs (NSAIDs) both increase the risk of upper gastrointestinal events (UGIEs). In the Netherlands, recommendations regarding the prescription of gastroprotective agents (GPAs) in LDA users were first issued in 2009 in the HARM-Wrestling consensus. National guidelines on gastroprotective strategies (GPSs) in NSAID users were issued in the first part of the preceding. The aim of the present study was to examine time-trends in GPSs in patients initiating LDA and those initiating NSAIDs between 2000 and 2012. METHODS: Within a large electronic primary healthcare database, two cohorts were selected: (i) patients newly prescribed LDA and (ii) patients newly prescribed NSAIDs between 2000 and 2012. Patients who had been prescribed a GPA in the previous six months were excluded. For both cohorts, patients' risk of a UGIE was classified as low, moderate or high, based on the HARM-Wrestling consensus, and the presence of an adequate GPSwas determined. RESULTS: A total of 37 578 patients were included in the LDA cohort and 352 025 patients in the NSAID cohort. In both cohorts, an increase in GPSs was observed over time, but prescription of GPAs was lower in the LDA cohort. By 2012, an adequate GPS was present in 31.8% of high-risk LDA initiators, vs. 48.0% of high-risk NSAID initiators. CONCLUSIONS: Despite a comparable risk of UGIEs, GPSs are prescribed less in high-risk LDA initiators than in high-risk NSAID initiators. For both groups of patients, there is still room for improvement in guideline adherence.

Pediatric drug safety signal detection: a new drug-event reference set for performance testing of data-mining methods and systems.

BACKGROUND: Better evidence regarding drug safety in the pediatric population might be generated from existing data sources such as spontaneous reporting systems and electronic healthcare records. The Global Research in Paediatrics (GRiP)-Network of Excellence aims to develop pediatric-specific methods that can be applied to these data sources. A reference set of positive and negative drug-event associations is required. OBJECTIVE: The aim of this study was to develop a pediatric-specific reference set of positive and negative drug-event associations. METHODS: Considering user patterns and expert opinion, 16 drugs that are used in individuals aged 0-18 years were selected and evaluated against 16 events, regarded as important safety outcomes. A cross-table of unique drug-event pairs was created. Each pair was classified as potential positive or negative control based on information from the drug's Summary of Product Characteristics and Micromedex. If both information sources consistently listed the event as an adverse event, the combination was reviewed as potential positive control. If both did not, the combination was evaluated as potential negative control. Further evaluation was based on published literature. RESULTS: Selected drugs include ibuprofen, flucloxacillin, domperidone, methylphenidate, montelukast, quinine, and cyproterone/ethinylestradiol. Selected events include bullous eruption, aplastic anemia, ventricular arrhythmia, sudden death, acute kidney injury, psychosis, and seizure. Altogether, 256 unique combinations were reviewed, yielding 37 positive (17 with evidence from the pediatric population and 20 with evidence from adults only) and 90 negative control pairs, with the remainder being unclassifiable. CONCLUSION: We propose a drug-event reference set that can be used to compare different signal detection methods in the pediatric population.