The choice of drugs is mainly linked to the identification of the type of seizure and epileptic syndrome. For patients with epilepsy, effective seizure control is the determining factor for a good quality of life. AED dosages must be individualized to maximize therapeutic effects and avoid side effects. The early childhood epilepsy syndrome such as DS, LGS and WS present no easy medical management due to the fact that subjects often show convulsion resistant to the available treatment. Therefore, of safe and effective therapies arenecessary to reduce the risk of neurological sequelae. The drugs preferentially used in particular forms of pediatric epilepsy are phenobarbital, phenytoin, benzodiazepine, topiramate, levetiracetam and valproic acid .
3. Common Antiepileptic Drugs
CBD: Cannabidiol; TEAEs: Treatment-emergent adverse events; SAEs: serious adverse events; AST: aspartate transferase; ALT: alanine transferase.
4. Cannabidiol and Molecular Targets in Epilepsy
The first clinical trial GWPCARE1 was divided into two parts: Part A ( <"type":"clinical-trial","attrs":<"text":"NCT02091206","term_id":"NCT02091206">> NCT02091206) and Part B ( <"type":"clinical-trial","attrs":<"text":"NCT02091375","term_id":"NCT02091375">> NCT02091375). <"type":"clinical-trial","attrs":<"text":"NCT02091206","term_id":"NCT02091206">> NCT02091206, a double-blind randomization study (phase 2), to evaluate the safety of multiple doses of the CBD oral solution (GWP42003-P) in 34 children (4 to 10 years) with DS. All patients before enrolment had to have stabilized all AEDs at least 1 month before and the therapy stability had to be maintained during the study. Participants were randomized to one of the three doses (5, 10 and 20 mg/kg/day) of active drug or placebo at a 4:1 ratio. In addition, patients had to take their usual dose of antiepileptic drugs 2 h before CBD administration. The primary outcome was to assess the incidence of Treatment-Emergent AEs (TEAEs). A pharmacokinetic evaluation was also performed by measuring the plasma concentrations of CBD and its metabolites 7-OH-CBD and 7-carboxycannabidiol (7-COOH-CBD), and of the most common antiepileptic drugs taken by patients. Serious TEAEs, such as pyrexia and convulsions, occurred in five patients: one at the dose of 5 mg/kg/day, two at the dose of 10 mg/kg/day, one at the dose of 20 mg/kg/day and one in the placebo group. No serious TEAEs (such as pyrexia, somnolence, decreased appetite, sedation, vomiting, ataxia and abnormal behaviour) reported in 80% of patients at 5 mg/kg/day of CBD, in 62.5% at the 10 mg/kg/day dose, in 77.78% at the 20 mg/kg/day dose and in 85.71% of placebo group. SAEs such as status epilepticus, convulsion, parvovirus infection, rash maculopapular, occurred in 10% of patients who received 5 mg/kg daily of CBD, in 25% at the 10 mg/kg daily, in 11.11% at the 20 mg/kg daily and in the 14.29% in placebo group. CBD was generally well-tolerated at the 5–20 mg/kg/day dose range. Elevated transaminases (ALT or AST) were only reported with concomitant use of valproate. The study showed that exposure to CBD and its metabolites increased in a dose-dependent manner, and 7-COOH-CBD was the most abundant circulating metabolite at all doses and times. In fact, at the end of treatment, 7-COOH-CBD levels were 13–17 times higher than those of CBD. The results also showed a pharmacokinetic interaction of CBD with CLB, resulting in an increment of the metabolite N-desmethylclobazam [N-CLB] in plasma exposure of the patients. An elevation in N-CLB, was absent in patients co-administered with stiripentol, possibly reflecting prior inhibition of the CYP2C19 isoenzyme .
Sample size: A total of 80 participants (40 assigned to treatment and 40 to control group) recruited from Toronto Western Hospital in Toronto, and University Hospital in London, Ontario.
Time: Each participant will be enrolled for approximately 16 to 18 weeks, while the clinical trial is expected to take place over a period of two years.