Roberto Caraballo etal. [825] presented eight patients with West syndrome who were refractory to ASMs, and who were treated with cannabidiol-enriched cannabis oil as add-on therapy. After a follow-up of between 6 and 13months, a 75–99% decrease in seizure frequency was observed in two patients, a 50–74% decrease was observed in two, a less than 50% decrease was observed in three, and no changes in seizure fre­quency were seen in the remaining patient. The index of EEG abnormalities improved between 20% and 80% in seven patients concurrently with the reduction in seizures.

Giselda Cabral-Pereira et al. [830] examined the behavioral and molecular effects of acute and chronic intraperitoneal administrations of VPA (300mg/kg) and CBD (100mg/kg) on the GASH/Sal audiogenic seizures (a reliable experimental model of generalized tonic–clonic seizures in response to intense sound stimula­tion). They found that acute and chronic CBD treatments have no signicant adverse effects on body weight, hematological parameters, and liver function, although locomotor activity was reduced.

Preclinical Research onCannabidiol

Merrick S Fallah etal. [833] assessed the efcacy of cannabidiol (CBD) and 9-tetrahydrocannabinol (THC) for suppressing focal and secondarily generalized seizures in an amygdala-kindling rat. It was found that CBD alone produced a par­tial suppression of both generalized seizures and focal seizures. THC alone also produced partial suppression of generalized and focal seizures, but doses of 10mg/ kg and above produced hypolocomotion. The addition of a low dose of THC to CBD (15:1) has antiseizure properties in the amygdala-kindling model. The addi­tion of small amounts of THC greatly improves the effectiveness of CBD.A combi­nation of CBD and THC might be useful for the management of focal impaired awareness seizures (FIASs).

Giselda Cabral-Pereira etal. [830] examined acute and chronic CBD administration in a hamster model of hereditary auditory convulsion, and found that chronic treatment with CBD caused abnormal mRNA expression levels for Trpv1, Adora1, Slc29a1, and Cnr1 genes. The study constituted a basis on which to develop further studies on the pharmacological effects of CBD and its interactions with other anticonvulsants.

Dose adjustment is required in patients taking concomitant stiripentol plus clo­bazam: the maximum daily maintenance dosage of fenuramine is 0.2mg/kg twice daily (maximum daily dosage of 17mg).

Dosage adjustment is recommended in patients taking strong CYP1A2 or CYP2D6 inhibitors, with severe renal impairment, or with mild, moderate, or severe hepatic impairment.

The most common adverse reactions (incidence at least 10% and greater than pla­cebo) in patients with Dravet Syndrome were decreased appetite, somnolence, seda­tion, lethargy, diarrhea, constipation, abnormal echocardiogram, fatigue, malaise, asthenia, ataxia, balance disorder, gait disturbance, blood pressure increase, drool­ing, salivary hypersecretion, pyrexia, upper respiratory tract infection, vomiting, decreased weight, fall, status epilepticus.

Fenuramine forDravet Syndrome

They concluded that in both trials, one in every two to three DS patients treated with fenuramine achieved a reduction in the number of episodes of ≥50% or ≥75% compared to placebo. Respondent analysis and NNTs can provide important information for clinical decision-making, supplementing the average number of individuals achieving meaningful levels of improvement in MCSF.

To investigate the association between reduced seizure frequency and daily executive function (EF) dose in children and young adults on fenuramine adju­vant therapy, Bishop etal. [845] performed a postmortem analysis of data from patients 5–18years of age with DS who were enrolled in a randomized, placebo­controlled Phase 3 clinical trial. A minimum 1year fenuramine Open Label Extension (OLE) study was subsequently completed. They found that a reduction of ≥50% in the daily frequency of attacks in 78% of patients. Overall, there was a signicant correlation between change in MCSF and change in the Behavior Rating Inventory of Executive Function (BRIEF) 2T scores for emotional regula­tion index (ERI) (p=0.008). The 50% MCSF reduction group was signicantly more likely to achieve clinically meaningful improvement in ERI (p=0.002) and in cognitive regulation index (CRI) (p=0.001) than the <50% MCSF reduction group. In summary, in children and young adults with DS, the magnitude of reduc­tion in MCSF after long-term treatment with adjunctive fenuramine was associ­ated with clinically meaningful levels of improvement in everyday EF.Seventy-eight percent of children and young adults treated with adjunctive fenuramine for 1year in the OLE study achieved a 50% reduction in MCSF, for a magnitude of efcacy associated with a signicantly greater likelihood of expe­riencing clinically meaningful improvement in emotion regulation and cognitive regulation.

Sullivan etal. [847] analyzed data from two phase 3 placebo-controlled trials of fenuramine adjuvant therapy for DS.They enrolled patients aged 2–19years who were randomized to receive placebo or the addition of fenuramine (Study 1:

Parthena etal. [849] examined the modulatory activity of fenuramine on the S1R­mediated antiamnesic response in mice using combination analyses. Fenuramine and norfenuramine, racemate and isomers, were combined with either the S1R agonist PRE-084 or the S1R-acting neuroactive steroids pregnenolone sulfate (PREGS), dehydroepiandrosterone sulfate (DHEAS), or progesterone.

They reported that fenuramine racemate or (+)-fenuramine, in the 0.1–1mg/ kg dose range, attenuated the dizocilpine-induced learning decits in spontaneous alternation and passive avoidance, and showed low-dose synergies in combination with PRE-084. These effects were blocked by the S1R antagonist NE-100. Dehydroepiandrosterone sulfate or PREGS attenuated dizocilpine-induced learning decits in the 5–20mg/kg dose range. Cotreatments at low doses between steroids and fenuramine or (+)-fenuramine were synergistic. Progesterone blocked fen­uramine’s effect. Finally, fenuramine and (+)-fenuramine effects were pre­vented by the addition of the 5-HT1A receptor antagonist WAY-100635 or the 5-HT2A antagonist RS-127445, but not by the 5-HT1B/1D antagonist GR 127935 or the 5-HT2C antagonist SB 242084, conrming a 5-HT1A and 5-HT2A receptor involvement in the drug effect on memory.