Development of Liquid Chromatography-Tandem Mass Spectrometry Methods of Cannabinoids for Pediatric Patient Samples
Notice bibliographique
Résumé
Thirty percent of pediatric epilepsies become resistant to conventional treatments, such as antiepileptic drugs and ketogenic diets. Growing anecdotal evidence of using Cannabis for treating epilepsy has prompted parents to acquire Cannabis products for their children without the consent or guidance of their pediatrician. Limited scientific based evidence exists for pediatric epilepsy and Cannabis therapy. Establishing a standard dosage regimen to ensure the safety and efficacy with Cannabis based medicine for pediatric epilepsy requires conducting a pharmacokinetic (PK) study to define the age-dependent pharmacokinetic parameters.\n The Cannabidiol and Children with Refractory Epileptic Encephalopathy (CARE-E) open-labelled dose escalation study utilizing a 1:20 delta9-tetrahydrocannabinol (THC): cannabidiol (CBD) Cannabis herbal extract containing 4% cannabichromene (CBC) will establish a recommended dose for the PK study and define the relationship between the minimum cannabinoid plasma concentration at steady state (Css,min) and dose. A sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was utilized to quantify the Css,min. Participant A-04 exhibited a greater than proportional increase in Css,min relative to the dose (10-12 mg/kg/day), indicating non-linear PK. No THC intoxication was observed during the study. All participants displayed linear pharmacokinetics and seizure frequency reductions at 5-6 mg/kg/day, recommending the 5-6 mg/kg/day dose to be used for the PK study. \n Ketogenic diets, a high fat diet used for pediatric epilepsy, may alter the plasma levels of lipoproteins, a major plasma protein in cannabinoid plasma protein binding. The unbound cannabinoid concentration is only able to produce a pharmacological effect; therefore, it is imperative to determine the effects ketogenic diets impart on protein binding to conclude if dosage adjustments are necessary. Cannabinoids may exhibit non-specific binding or buffer solubility issues observed with the commonly used plasma protein binding assays. A novel 3-extraction technique was developed for lipophilic compounds to avoid these issues. A comparative analysis was conducted between commonly used techniques (ultrafiltration and rapid equilibrium dialysis) and the 3-solvent extraction technique, with the 3-solvent extraction technique providing higher cannabinoid recovery and assay reproducibility, indicating 82.7%, 82.1%, 87.0%, and 93.4% plasma protein binding of 11-OH-THC, CBD, THC, and CBC, respectively. \n With legalization of recreational Cannabis, there has been growing concern over pregnant women consuming Cannabis. Cannabinoids can cross the blood placental barrier and reach the fetal systemic circulation. Increased Cannabis use during pregnancy would be a public health concern; therefore, it is crucial to determine the prevalence of prenatal Cannabis exposure. This was determined using residual neonate dried blood spot (DBS) screening cards collected from April, May, and June 2018 (pre-legalization) and April, May, and June 2019 (post-legalization). Due to its long half-life 11-nor-9- carboxy-delta9-tetrahydrocannabinol (THC-COOH), an inactive THC metabolite, is a suitable drug marker for Cannabis exposure. A quantitative LC-MS/MS assay was initially developed, however, factors such as hematocrit effect, chromatographic effect, and sample heterogeneity contributed to inaccurate and imprecise cannabinoid quantification. Alternatively, a qualitative LC-MS/MS assay, which solely utilizes a limit of detection (LOD), was applied, establishing a LOD of 1.47 ng/mL. Currently, we detected THC-COOH in 11 of 220 Saskatchewan residual neonate DBS cards collected pre-legalization, indicating a 5% prenatal Cannabis exposure rate. \n The recommended dose obtained from the CARE-E dose escalation study and the LC-MS/MS assay will be utilized in single oral dose pharmacokinetic studies in the pediatric population to characterize the required age dependent pharmacokinetic parameters for establishing a standard dosage regimen. The 3-solvent extraction technique will determine the influence ketogenic diets have on the cannabinoid plasma protein binding profile and if dosage adjustments are necessary. Complete analysis of the pre- and post-legalization Saskatchewan, Manitoba, and British Columbia residual neonate dried blood spot samples will establish the prevalence of prenatal Cannabis exposure in each province.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,005 | 0,008 |
| Méta-épidémiologie (sens strict) | 0,002 | 0,001 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,005 | 0,002 |
| Études des sciences et des technologies | 0,002 | 0,001 |
| Communication savante | 0,002 | 0,001 |
| Science ouverte | 0,002 | 0,001 |
| Intégrité de la recherche | 0,002 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,007 | 0,006 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».