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BackgroundCisplatin, a chemotherapy used to treat solid tumors, causes acute kidney injury (AKI), a known risk factor for chronic kidney disease and mortality. AKI diagnosis relies on biomarkers which are only measurable after kidney damage has occurred and functional impairment is apparent; this prevents timely AKI diagnosis and treatment. Metabolomics seeks to identify metabolite patterns involved in cell tissue metabolism related to disease or patient factors. The A Canadian study of Cisplatin mEtabolomics and NephroToxicity (ACCENT) team was established to harness the power of metabolomics to identify novel biomarkers that predict risk and discriminate for presence of cisplatin nephrotoxicity, so that early intervention strategies to mitigate onset and severity of AKI can be implemented.ObjectiveDescribe the design and methods of the ACCENT study which aims to identify and validate metabolomic profiles in urine and serum associated with risk for cisplatin-mediated nephrotoxicity in children and adults.DesignObservational prospective cohort study.SettingSix Canadian oncology centers (3 pediatric, 1 adult and 2 both).PatientsThree hundred adults and 300 children planned to receive cisplatin therapy.MeasurementsDuring two cisplatin infusion cycles, serum and urine will be measured for creatinine and electrolytes to ascertain AKI. Many patient and disease variables will be collected prospectively at baseline and throughout therapy. Metabolomic analyses of serum and urine will be done using mass spectrometry. An untargeted metabolomics approach will be used to analyze serum and urine samples before and after cisplatin infusions to identify candidate biomarkers of cisplatin AKI. Candidate metabolites will be validated using an independent cohort.MethodsPatients will be recruited before their first cycle of cisplatin. Blood and urine will be collected at specified time points before and after cisplatin during the first infusion and an infusion later during cancer treatment. The primary outcome is AKI, defined using a traditional serum creatinine-based definition and an electrolyte abnormality-based definition. Chart review 3 months after cisplatin therapy end will be conducted to document kidney health and survival.LimitationsIt may not be possible to adjust for all measured and unmeasured confounders when evaluating prediction of AKI using metabolite profiles. Collection of data across multiple sites will be a challenge.ConclusionsACCENT is the largest study of children and adults treated with cisplatin and aims to reimagine the current model for AKI diagnoses using metabolomics. The identification of biomarkers predicting and detecting AKI in children and adults treated with cisplatin can greatly inform future clinical investigations and practices.

Drug hypersensitivity reactions (DHRs) are type B adverse drug reactions (ADRs) traditionally defined as unpredictable, dose independent and not related to the drug pharmacology. DHRs, also called drug allergy if the immune system involvement is confirmed, represent around one‐sixth of all ADRs and can cause major clinical problems due to their vague clinical presentation and irregular time course. Understanding the underlying pathophysiology of DHRs is very important for their diagnosis and management. Multiple layers of evidence exist pointing to the involvement of the immune system in DHRs. Recent data have led to a paradigm shift in our understanding of the exact pathophysiology of these reactions. Numerous hypotheses proposing explanation on how a low molecular weight drug molecule can elicit an immune reaction have been proposed. In addition to the classical "hapten" hypothesis, the reactive metabolite hypothesis, the pharmacological interaction with the immune system (p‐i) concept, the danger/injury hypothesis and the altered peptide repertoire hypothesis have been proposed. We here introduce the inflammasome activation hypothesis and the cross‐reactivity hypothesis as additional models explaining the pathophysiology of DHRs. Available data supporting these hypotheses are briefly summarized and discussed. We also introduced the cross‐reactivity model, which may provide a platform to appreciate the potential role played by other factors leading to the activation of the immune system. We believe that although the drug in question could be the trigger of the reaction, the components of the immune system mediating the reaction do not act in isolation but rather are affected by the proinflammatory milieu occurring at the time of the reaction. This review attempts to summarize the available evidence to further illustrate the pathophysiology of DHRs. [ABSTRACT FROM AUTHOR]

Aim: Cisplatin causes acute kidney injury (AKI) in approximately one third of patients. Serum creatinine and urinary output are poor markers of cisplatin‐induced AKI. Metabolomics was utilized to identify predictive or early diagnostic biomarkers of cisplatin‐induced AKI. Methods: Thirty‐one adult head and neck cancer patients receiving cisplatin (dose ≥70 mg/m2) were recruited for metabolomics analysis. Urine and serum samples were collected prior to cisplatin (pre), 24–48 h after cisplatin (24–48 h) and 5–14 days (post) after cisplatin. Based on serum creatinine concentrations measured at the post timepoint, 11/31 patients were classified with clinical AKI. Untargeted metabolomics was performed using liquid chromatography‐mass spectrometry (LC‐MS). Results: Metabolic discrimination was observed between "AKI" patients and "no AKI" patients at all timepoints. Urinary glycine, hippuric acid sulfate, 3‐hydroxydecanedioc acid and suberate were significantly different between AKI patients and no AKI patients prior to cisplatin infusion. Urinary glycine and hippuric acid sulfate were lower (−2.22‐fold and −8.85‐fold), whereas 3‐hydroxydecanedioc acid and suberate were higher (3.62‐fold and 1.91‐fold) in AKI patients relative to no AKI patients. Several urine and serum metabolites were found to be altered 24–48 h following cisplatin infusion, particularly metabolites involved with mitochondrial energetics. Conclusions: We propose glycine, hippuric acid sulfate, 3‐hydroxydecanedioc acid and suberate as predictive biomarkers of predisposition to cisplatin‐induced AKI. Metabolites indicative of mitochondrial dysfunction may serve as early markers of subclinical AKI. [ABSTRACT FROM AUTHOR]

L'intérêt envers l'utilisation des produits du cannabis à des fins médicales chez les enfants de moins de 18 ans augmente. De nombreux produits du cannabis à des fins médicales contiennent du cannabidiol, du delta-9-tétrahydrocannabinol ou ces deux produits. Malgré les nombreuses prétentions thérapeutiques, peu d'études rigoureuses guident la posologie, l'innocuité et l'efficacité du cannabis à des fins médicales en pédiatrie clinique. Le présent document de principes passe en revue les données probantes à jour et expose les recommandations sur l'utilisation du cannabis à des fins médicales chez les enfants. Les rapports à plus long terme (deux ans) souscrivent à la tolérabilité et à l'efficacité soutenues d'un traitement au cannabidiol chez les patients ayant le syndrome de Lennox-Gastaut ou le syndrome de Dravet. Les extraits de cannabis enrichis de cannabidiol qui renferment de petites quantités de delta-9-tétrahydrocannabinol ont été évalués auprès d'un petit nombre de patients d'âge pédiatrique, et d'autres recherches devront être réalisées pour éclairer les guides de pratique clinique. Étant donné l'utilisation répandue du cannabis à des fins médicales au Canada, les pédiatres devraient être prêts à participer à des échanges ouverts et continus avec les familles au sujet de ses avantages potentiels et de ses risques, ainsi qu'à préparer des plans individuels en vue d'en surveiller l'efficacité, de réduire les méfaits et de limiter les interactions médicamenteuses. [ABSTRACT FROM AUTHOR]

Interest in using cannabis products for a medical purpose in children under the age of 18 years is increasing. There are many medical cannabis products available that can include cannabidiol (CBD) or delta-9-tetrahydrocannabinol (THC), or both. Despite many therapeutic claims, there are few rigorous studies to inform the dosing, safety, and efficacy of medical cannabis in paediatric clinical practice. This statement reviews the current evidence and provides recommendations for using medical cannabis in children. Longer-term (2-year) reports support the sustained tolerability and efficacy of cannabidiol therapy for patients with Lennox-Gastaut and Dravet syndromes. CBD-enriched cannabis extracts containing small amounts of THC have been evaluated in a small number of paediatric patients, and further research is needed to inform clinical practice guidelines. Given the widespread use of medical cannabis in Canada, paediatricians should be prepared to engage in open, ongoing discussions with families about its potential benefits and risks, and develop individualized plans that monitor efficacy, reduce harms, and mitigate drug–drug interactions. [ABSTRACT FROM AUTHOR]

This article discusses the past, present, and future of drug safety. It highlights the shift from traditional beliefs and anecdotal reports to evidence-based medicine in drug therapy. The article emphasizes the importance of understanding drug harms and their detection, with a focus on topics such as pharmacogenetics, metabolomics, and pharmacovigilance. It also addresses medication errors, the importance of post-marketing studies, and drug reactions related to the skin. The authors conclude that clinical pharmacologists and clinicians need to continue studying drug safety to ensure safe and effective drug use. [Extracted from the article]