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Background Cannabidiol (CBD), which is one major constituent of the Cannabis sativa plant, has anti-seizure properties and does not produce euphoric or intrusive side effects. A plant-derived, highly purified CBD formulation with a known and constant composition has been approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome, Lennox–Gastaut syndrome, and tuberous sclerosis complex. In the European Union, the drug has been authorized by the European Medicines Agency for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome, in conjunction with clobazam, and is under regulatory review for the treatment of seizures in patients with tuberous sclerosis complex. Objectives This systematic review aimed to summarize the currently available body of knowledge about the use of this US Food and Drug Administration/European Medicines Agency-approved oral formulation of pharmaceutical-grade CBD in patients with epileptic conditions, especially developmental and epileptic encephalopathies other than Dravet syndrome and Lennox–Gastaut syndrome. Methods The relevant studies were identified through MEDLINE and the US National Institutes of Health Clinical Trials Registry in October 2020. There were no date limitations or language restrictions. The following types of studies were included: clinical trials, cohorts, case-control, cross-sectional, clinical series, and case reports. Participants had to meet the following criteria: any sex, any ethnicity, any age, diagnosis of epilepsy, receiving plant-derived, highly purified (> 98% w/w) CBD in a sesame oil-based oral solution for the treatment of seizures. Data extracted from selected records included efficacy, tolerability, and safety outcomes. Results Five hundred and seventy records were identified by database and trial register searching. Fifty-seven studies were retrieved for detailed assessment, of which 42 were eventually included for the review. The participants of the studies included patients of both pediatric and adult age. Across the trials, purified CBD was administered at dosages up to 50 mg/kg/day. In a randomized double-blind controlled trial in patients with tuberous sclerosis complex, CBD was associated with a significantly greater percent reduction in seizure frequency than placebo over the treatment period. Open-label studies suggested the effectiveness of CBD in the treatment of children and adults presenting with other epilepsy syndromes than those addressed by regulatory trials, including CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes, SYNGAP1 encephalopathy, and epilepsy with myoclonic absences. The most common adverse events observed during treatment with CBD included somnolence, decreased appetite, diarrhea, and increased serum aminotransferases. Conclusions The currently available data suggest that response to treatment with a highly purified, plant-derived CBD oil-based solution can be seen in patients across a broad range of epilepsy disorders and etiologies. The existing evidence can provide preliminary support for additional research. Supplementary Information The online version contains supplementary material available at 10.1007/s40263-021-00807-y.

OBJECTIVES The objective of this study was to evaluate seizure remission rates in patients with benign epilepsy of childhood with centrotemporal spikes (BECTS) receiving antiepileptic drugs. METHODS PubMed and Web of Science were searched for studies on pharmacotherapy in patients with BECTS using free search terms or Medical Subject Headings. Only studies that used seizure-freedom rates as an indicator for pharmaceutical efficacy were considered. Different antiepileptic drugs were compared using the Fisher exact test for seizure-freedom rates. RESULTS A total of 19 studies were included, 6 of them being randomized controlled trials. The randomized controlled trials included a total of 308 patients and covered sulthiame (n = 52), topiramate (n = 45), levetiracetam (n = 43), oxcarbazepine (n = 31), carbamazepine (n = 68), and clobazam (n = 18) as well as placebo (n = 35) and untreated control groups (n = 16). Treatment success rates were significantly higher in those children treated with sulthiame, levetiracetam, and clobazam compared with the children treated with carbamazepine, oxcarbazepine, or topiramate. CONCLUSIONS The available literature suggests the use of sulthiame, levetiracetam, or clobazam as first-line agents for the treatment of BECTS.

The study attempts to characterize the clinical, demographic, risk factors, electroencephalographical, and neuroimaging features of hot-water epilepsy (HWE) in children. This is a hospital-based observational study in the pediatric neurology clinic and who met the clinical definition of hot-water epilepsy were studied from January 2017 to October 2018. Clinical history, demographic data, and examination findings were recorded in a pre-structured proforma. Electroencephalography (EEG) and neuroimaging were carried out. A total of 68 children with male to female ratio of 2.4:1 were studied. The most common age of onset of seizures was between 1 and 5 y. Focal seizures with impaired awareness were the most common semiology (48.5%). Abnormal EEG was detected in 13.2% and abnormal neuroimaging in 4.4% which consisted of incidental abnormalities. Nonreflex seizures occurred in 35.3% of the children with HWE and the risk factors associated with this were not statistically significant. Clobazam before taking bath helped to achieve seizure control in 85.7% of the children. Hot-water epilepsy should be suspected in children who develop seizures following a hot-water bath. The most common age of onset is 1–5 y. EEG and neuroimaging are normal in the majority of cases. Nonreflex seizures occurred in 35.3% of the children.

Angelman Syndrome (AS) is characterized by severe developmental delays including marked speech impairment, movement abnormalities(ataxia, tremor), and unique behaviors such as frequent laughter and is caused by dysfunctional maternal UBE3A gene (maternal 15q11-13 deletions, maternal specific UBE3A mutation, uniparental disomy, and imprinting defect). Intractable epileptic seizures since early childhood with characteristic EEG abnormalities are present in 80–90% patients with AS. Underlying pathophysiology may involve neocortical and thalamocortical hyperexcitability secondary to severe reduction of GABAergic input, as well as dysfunctional synaptic plasticity, deficient synaptogenesis, and neuronal morphological immaturity. The onset of epilepsy is most prevalent between 1 and 3 years of age; however, approximately 25% of patients developed epilepsy before one year of age. Various types of generalized seizures are most prevalent, with most common types are myoclonic and atypical absence. More than 95% of epilepsy patients may have daily seizures at least for a limited time during early childhood, and two-third patients develop disabling seizures. Fever provoked seizures, and frequent occurrence of nonconvulsive status epilepticus are two unique features. Seizures are frequently pharmacoresistant. Considering underlying prominent GABAergic dysfunction, clinicians had used AEDs that target GABAergic signaling such as valproate, phenobarbital, and clonazepam as first-line therapies for AS. However, due to the unfavorable side effect profile of these AEDs, a recent treatment approach involves priority use of levetiracetam, clobazam, topiramate, lamotrigine, ethosuximide, VNS, and carbohydrate-restricted diets. Besides symptomatic management, there has been recent progress to find a curative treatment with the following approaches: 1. Gene/protein replacement therapy (Adeno and lentiviral vector therapy to deliver a gene or secretory protein); 2. Activation of the intact but silent paternal copy of UBE3A (antisense oligonucleotide therapy and artificial transcription factors); and 3. Downstream therapies (OV101/gaboxadol, ketone supplement, novel compounds/peptides, anti-inflammatory/regenerative therapy).

Background: Patients with epilepsy have a higher mortality rate than the general population. Up-to-date estimates of epilepsy incidence, prevalence, and medication use are critical to assist policymaking. Methods: Using the National Taiwan Insurance Research Database, the standardized incidence and prevalence of epilepsy were estimated in each calendar year from 2007 to 2015. We used the incident cases of epilepsy to analyze the change in prescribing patterns from 2007 to 2015. Joinpoint regression was used to estimate secular trends. Results: From 2007 to 2015, the age- and sex-standardized incidence decreased from 0.72 (95% confidence interval [CI] 0.70–0.73) to 0.54 (95% CI 0.53–0.55) per 1,000 person-years, giving an annual percentage change (APC) of −2.73 (p < 0.05). Among patients younger than 20 years, the incidence did not change significantly. The age- and sex-standardized prevalence decreased from 6.94 (95% CI 6.90–6.98) to 6.86 (95% CI, 6.82–6.89) per 1,000 people, giving an APC of −0.31 (p < 0.05). However, the prevalence increased in the 35- to 49- and 50- to 64-year age-groups. The most common first-line anticonvulsant was phenytoin in 2007 and valproate in 2015. The use of levetiracetam, clobazam, and valproate increased during the study period, with APCs of 25.48% (95% CI 19.97–31.24), 6.41 (3.09–9.85), and 2.83 (1.51–4.16), respectively. The use of carbamazepine, phenytoin, and topiramate decreased; the APCs were −23.86% (95% CI −25.25 to −22.44), −6.61 (−8.40 to −4.79), and −4.29% (−7.87 to −0.57), respectively. Conclusions: The overall prevalence and incidence of epilepsy decreased slightly from 2007 to 2015. The prescribed first-line anticonvulsant also changed over time.

We aimed to determine the morphological and histological effects of zonisamide, sultiam, lacosamide, clobazam, and rufinamide on ovarian folliculogenesis in rats. Sixty female Wistar rats were divided into six experimental groups as control, zonisamide, sultiam, lacosamide, clobazam, and rufinamide groups; control solution and drugs were administered by gavage for 90 days. The number of healthy follicles in the control group was significantly higher than in the anti-medication groups (p 0.001), and the number of corpus luteum was significantly lower (p 0.001). There was a significant difference in the number of TUNEL positive apoptotic follicles between the control and drug groups (p 0.001). With EGF, IGF-1, and GDF-9 staining, a very strong immunoreaction was observed in the ovarian multilaminar primary follicle granulosa cells and oocytes in the control group compared to the drug group (p 0.001). Long-term anti-seizure medication with zonisamide, sultiam, lacosamide, clobazam, and rufinamide from prepubertal to adulthood causes apoptosis and disruption of folliculogenesis in the ovarian follicles of nonepileptic rats.

Objective: To evaluate the effectiveness and tolerability of clobazam therapy in the pediatric population in terms of seizure semiology, epileptic syndromes, and etiological subgroups. Methods: A retrospective cohort study was conducted consisting of 1710 epileptic children from eight centers in seven geographic regions of Turkey. The initial efficacy of clobazam therapy was evaluated after three months of treatment. The long-term effectiveness of the drug, overall seizure outcomes, and overall therapeutic outcomes were evaluated during 12 months of therapy. Results: Analysis of initial efficacy after the first three months of clobazam therapy showed that 320 (18.7 %) patients were seizure-free, 683 (39.9 %) had > 50 % seizure reductions, and 297 (17.4 %) had < 50 % seizure reductions. A positive response (seizure-free and >50 % seizure reduction) was determined for focal-onset (62.3 %) seizures, epileptic spasms (61.5 %), and generalized onset seisures (57.4). The highest positive response rate among the epileptıc syndromes was for self-limited epilepsy with centrotemporal spikes (SeLECTS). The highest negative response rate was for developmental and/or epileptic encephalopathies (DEEs). Magnetic resonance imaging (MRI) revealed a structural etiological diagnosis in 25.8 % of the cohort. A higher positive response rate was observed at MRI in patients with sequelae lesions than in those with congenital lesions. The seizure recurrence rate was higher in the patient group with epilepsy wıth genetic and metabolic causes, in individuals with more than one seizure type, and in those using three or more antiseizure drugs. Conclusions: This cohort study provides additional evidence that clobazam is an effective and well-tolerable drug with a high seizure-free rate (18.7 %), a significant seizure reduction rate (57.3 %), and with excellent overall therapeutic outcomes with a low seizure relapse rate and considerable reversible benefits in the pediatric population.

ObjectivesTo evaluate the effectiveness and tolerability of clobazam as an adjunctive treatment for adults with drug-resistant epilepsy.MethodsWe performed a single-center, retrospective chart review of patients aged ≥18 years with drug-resistant epilepsy who started clobazam between 2010 and 2018. Included patients had outpatient visits both before and ≥1 month after clobazam initiation. Epilepsy classification, seizure frequency before and after clobazam, duration of clobazam treatment, and adverse effects were analyzed.ResultsA total of 417 patients met the inclusion criteria. Mean age was 37.5 years, and 54% of patients were female. Patients were on a mean of 2.4 antiepileptic drugs at the time of initiation of clobazam. Epilepsy types were focal (56.8%), Lennox-Gastaut syndrome (LGS) (21.1%), generalized (15.1%), and unclassified (7.0%). At the first follow-up visit ≥1 month after clobazam initiation, 50.3% of patients had >50% reduction in seizure frequency, and 20.5% were seizure free. Of the initial cohort, 17.1% were followed >1 year and were seizure free at last follow-up. Response rates did not differ between different epilepsy classifications. Fifty-one percent of patients experienced ≥1 side effect, most commonly lethargy/fatigue (30.7%) or mood changes (10.8%). A total of 178 (42.6%) patients discontinued clobazam, most commonly due to adverse effects (55%).ConclusionsClobazam is effective and safe as a long-term adjunctive therapy for adults with drug-resistant epilepsy; efficacy in off-label use is similar to that in LGS.Classification of EvidenceThis study provides Class IV evidence that clobazam is an effective treatment for adults with drug-resistant epilepsy, independent of epilepsy classification.

Resumen El tétanos generalizado es una enfermedad infecciosa altamente mortal sin intervenciones médicas y en nuestro tiempo, prevenible mediante inmunización activa. Se presenta el caso de un preescolar de 4 años quien sufre herida cortante en la palma de la mano izquierda y quien se presenta 4 días más tarde con datos clínicos de tétanos generalizado. Fue intubado y admitido a la terapia intensiva del Hospital del Niño Dr. José Renán Esquivel. Su hospitalización se vio caracterizada por neumonía nosocomial, una lesión anfractuosa lingual e inestabilidad autonómica. Además de la antibioticoterapia con metronidazol y la aplicación de inmunoglobulina antitetánica, precisó apoyo hemodinámico con dobutamina y norepinefrina. Para lograr un completo control de las crisis de hipertonía, se ofreció manejo con infusión de midazolam, levetiracetam, clobazam, baclofeno y toxina botulínica. Palabras clave: tétanos generalizado, inmunización, inestabilidad autonómica, opistótonos, trismos.

Objectives To assess the efficacy and safety profile of add-on cannabidiol (CBD) in patients with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) on clobazam and in the overall population of four randomized, controlled phase 3 trials. Methods Patients received plant-derived, highly purified CBD medicine (Epidiolex® in US; Epidyolex® in Europe; 100 mg/mL oral solution) at a dose of 10 or 20 mg/kg/day, or placebo for 14 weeks. A subgroup analysis of patients on clobazam and meta-analysis by syndrome were conducted. The primary endpoint was percentage reduction in primary seizure type during the treatment period. Results 396 patients with LGS (49% on clobazam) and 318 patients with DS (64% on clobazam) were included. CBD treatment resulted in a reduction in primary seizure frequency vs placebo in the overall population (treatment ratio [95% confidence interval]: LGS, 0.70 [0.62-0.80]; DS, 0.71 [0.60-0.83]) and in patients receiving clobazam (LGS, 0.56 [0.47-0.67]; DS, 0.63 [0.52-0.77]). The antiseizure efficacy of CBD was also demonstrated across other endpoints vs placebo (≥50% responder rate, total seizure frequency, number of seizure-free days, and Subject/Caregiver Global Impression of Change scores) in the overall populations and in patients receiving clobazam. There were higher incidences of somnolence and sedation in patients on CBD and clobazam. Most incidences of elevated transaminases occurred in patients on concomitant valproate and, to a lesser extent, clobazam. Conclusions Add-on CBD was effective in reducing seizures in the overall populations and in conjunction with clobazam. Somnolence and sedation occurred more frequently in patients on CBD and clobazam.

The use of therapeutic drug monitoring (TDM) for antiseizure medications (ASMs) may contribute to treatment optimization in individual patients. This study included patients with Dravet syndrome as they often require close monitoring because of polypharmacy with various ASMs. The aim was to use long-term TDM to investigate pharmacokinetic variability of ASMs in these patients.Retrospective data from patients with Dravet syndrome were collected from the TDM database at the Section for Clinical Pharmacology, National Center for Epilepsy in Norway (2008-2018). Concentration/(dose/kg)ratios (C/D ratios) were calculated for the ASMs and the concentration (C/C ratio) for N-desmethylclobazam. In patients with at least 3 measurements, the CV for C/D ratios for intrapatient and interpatient variability was calculated.Fifty-three patients (30 male patients/23 female patients) between 2 and 50 years of age (mean, 16 years) were included. Pharmacokinetic variability of the total number of measurements of valproate (n = 417), clobazam and N-desmethylclobazam (n = 328), and levetiracetam (n = 238) was determined. Interpatient variability was more pronounced than intrapatient variability (coefficient of variations: valproate, 65% vs. 24%; levetiracetam, 71% vs. 27%; and clobazam/N-desmethylclobazam, 47%/77% vs. 35%/55%) (P0.01). Comedication with stiripentol (n = 16) increased the C/D ratio of valproate by 63% and of clobazam by 133% and the C/C ratio of N-desmethylclobazam/clobazam by 104% (P0.05). Younger age also contributed to pharmacokinetic variability.Long-term TDM revealed extensive variability in serum concentrations over time; the variability was lowest for levetiracetam, moderate for valproate, and highest for clobazam. Pharmacokinetic variability and interactions can thus be identified and adjusted to facilitate decision making to achieve the optimal treatment outcome.

GW Research Ltd. provided two separate, but similar, submissions to the National Institute for Health and Care Excellence (NICE) on the clinical and cost-effectiveness of cannabidiol (CBD) 10 mg/kg/day, trade name Epidyolex(R), for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS). This paper highlights important methodological issues related to the company submissions, the Evidence Review Group (ERG) reports, and the subsequent development of the NICE guidance by the Appraisal Committee (AC) for the use of CBD. The company identified four randomised controlled trials (RCTs) of CBD (GWPCARE1 and GWPCARE2 for DS, and GWPCARE3 and GWPCARE4 for LGS) and an ongoing open-label extension study (GWPCARE5) as relevant to both submissions. In these RCTs, CBD in addition to current clinical management (CCM) was compared to CCM without CBD (i.e. CCM plus placebo). GWPCARE2 and GWPCARE3 were three-arm studies and compared two dosages of CBD (10 mg/kg/day and 20 mg/kg/day) in addition to CCM and CCM plus placebo. GWPCARE1 and GWPCARE4 compared CBD (20 mg/kg/day) in addition to CCM and CCM plus placebo. Both DS patients in GWPCARE2 and LGS patients in GWPCARE3 who received 10 mg/kg/day CBD in addition to CCM achieved better seizure frequency outcomes than those who received CCM plus placebo. In the company's base case, use of CBD for LGS patients resulted in an incremental cost-effectiveness ratio (ICER) of 31,107 pound per quality-adjusted life year (QALY) gained and, for DS patients, 36,046 pound per QALY gained versus CCM. The ERG considered that these ICERs were extremely uncertain and suffered from validity issues concerning model structure (e.g. patients receiving CCM moved back to baseline drop seizure frequency), input (e.g. inclusion of caregivers' QALYs), and transparency issues (e.g. hidden worksheets and coding in Visual Basic for Applications), and hence incorporated adjustments to the original base case which increased the ICERs. During the process, the European Medicines Agency (EMA) licence granted marketing authorisation for CBD only in conjunction with clobazam. Hence, the company provided evidence from this subgroup in an additional submission, which resulted in an ICER of 33,721 pound per QALY gained for LGS and an ICER of 32,471 pound per QALY gained for DS. In this submission and clarifications, the ERG was able to verify and validate most of the company's responses to the ERG's concerns. However, some issues remained regarding the face validity of model assumptions on patient pathways after treatment discontinuation. Finally, the AC recommended CBD with clobazam as an option for treating seizures associated with LGS and DS in patients aged 2 years and older only if (1) the frequency of drop seizures is checked every 6 months and CBD is stopped if the frequency has not fallen by at least 30% compared with 6 months before starting treatment and (2) the company provides CBD according to the commercial arrangement.

Objective: Dravet syndrome is a developmental and epileptic encephalopathy characterized by severe and drug-resistant seizures in early childhood, followed by developmental delay. The purpose of this study was to investigate aspects of pharmacological treatment of Norwegian patients with Dravet syndrome, focusing on the use of antiseizure medicines (ASMs) and identifying treatment challenges. Methods: Patients were identified through medical registries at the National Center for Epilepsy in Norway and National Center for Rare Epilepsy Related Disorders during 2008-2018. Additional clinical data were obtained from medical records and laboratory request forms. Results: We identified 53 patients with Dravet syndrome, 30/23 males/females, aged 2-50 years. The majority of patients with known seizure frequency experienced frequent seizures, 80% (n = 35/44). Only two patients were seizure-free. Valproate (n = 48), clobazam (n = 45), levetiracetam (n = 30), and stiripentol (n = 38) were most commonly used, previous or current use. More than one-third (n = 20) had tried sodium channel blockers (including lamotrigine), but these drugs were used less during the last decade. Polytherapy was common, 81% (n = 43) used two or more ASMs, and eight of these patients used 4-5 drugs (15%). Several challenges were identified: high seizure frequency, comorbidities, treatment changes with a wide range of ASMs, common use of oral gastro-tubes, extensive polypharmacy, and drug interactions. Significance: The use of ASMs has changed over the last decade, in accordance with updated international recommendations. Various treatment challenges were identified. This vulnerable group of patients needs close follow-up for an optimal treatment outcome. The Norwegian Epilepsy Association provided a research grant to the project.

Highly purified cannabidiol (CBD) has demonstrated efficacy with an acceptable safety profile in patients with Lennox‐Gastaut syndrome or Dravet syndrome in randomized, double‐blind, add‐on, controlled phase 3 trials. It is important to consider the possibility of drug‐drug interactions (DDIs). Here, we review six trials of CBD (Epidiolex/Epidyolex; 100 mg/mL oral solution) in healthy volunteers or patients with epilepsy, which investigated potential interactions between CBD and enzymes involved in drug metabolism of common antiseizure drugs (ASDs). CBD did not affect CYP3A4 activity. Induction of CYP3A4 and CYP2C19 led to small reductions in exposure to CBD and its major metabolites. Inhibition of CYP3A4 activity did not affect CBD exposure and caused small increases in exposure to CBD metabolites. Inhibition of CYP2C19 activity led to a small increase in exposure to CBD and small decreases in exposure to CBD metabolites. One potentially clinically important DDI was identified: combination of CBD and clobazam (CLB) did not affect CBD or CLB exposure, but increased exposure to major metabolites of both compounds. Reduction of CLB dose may be considered if adverse reactions known to occur with CLB are experienced when it is coadministered with CBD. There was a small increase of exposure to stiripentol (STP) when coadministered with CBD. STP had no effect on CBD exposure but led to minor decreases in exposure to CBD metabolites. Combination of CBD and valproate (VPA) did not cause clinically important changes in the pharmacokinetics of either drug, or 2‐propyl‐4‐pentenoic acid. Concomitant VPA caused small increases in exposure to CBD metabolites. Dose adjustments are not likely to be necessary when CBD is combined with STP or VPA. The safety results from these trials were consistent with the known safety profile of CBD. These trials indicate an overall low potential for DDIs between CBD and other ASDs, except for CLB.

The aim of this article is to provide a systematic and updated review on the pharmacology of cannabidiol in the context of refractory epilepsy, with special emphasis on its pharmacokinetics, adverse drug reactions and drug-drug interactions.A review of the literature related to cannabidiol pharmacokinetics, adverse drug reactions and drug-drug interactions was carried out in the context of refractory epilepsy, through a search in PubMed and LILACS.Original studies that exhaustively describe the pharmacokinetics of cannabidiol are limited but informative. Cannabidiol is rapidly absorbed and its bioavailability increases when administered with high fat meals. Cannabidiol exhibits a linear pharmacokinetic profile for doses up to 3,000 mg/day and accumulates after multiple administrations. Elimination half-life has been reported between 14 h and 60 h depending on the sampling times of each study; changes in cannabidiol elimination due to continuous administration cannot be discarded. Of all reported drugdrug interactions with anticonvulsants or other co-administered drugs in patients with epilepsy, the strongest evidence is provided with clobazam. The most frequent cannabidiol-related adverse drug reactions were low to moderate and included somnolence, mainly related to concomitant administration of clobazam, and gastrointestinal alterations. Also, liver function abnormalities were reported during the use of cannabidiol and valproic acid.Given the increased use of cannabidiol in refractory epilepsy, a comprehensive understanding of its pharmacological profile is essential for the clinical team. Specifically, clinical pharmacists play an important role in monitoring cannabidiol's safety and efficacy. This approach leads to treatment optimization, allowing to maximizing the pharmacological activity and minimizing the occurrence of adverse events as well as drug-to-drug interactions. Clinical follow-up is essential to avoid discontinuation of treatment or exacerbation of adverse events, which may impair the patients' quality of life.Objetivo: El objetivo del presente trabajo es brindar una revisión sistemática y actualizada acerca de la farmacología de cannabidiol, con especial énfasis en la farmacocinética, eventos adversos e interacciones, vinculada al uso de este fármaco en epilepsias refractarias.Método: Se realizó una revisión de los trabajos publicados y relacionados con la farmacocinética y los eventos adversos e interacciones farmacológicas de cannabidiol utilizado para el tratamiento de las epilepsias refractarias mediante una búsqueda en PubMed y LILACS.Resultados: Los estudios originales que describen la farmacocinética de cannabidiol de manera exhaustiva son limitados aunque informativos. La absorción de cannabidiol es rápida y se incrementa la biodisponibilidad por la ingesta conjunta de comidas ricas en grasas. El cannabidiol presenta farmacocinética lineal hasta dosis de 3.000 mg/día y se acumula por la administración continua. La semivida de eliminación se referencia entre 14 y 60 horas dependiendo de los tiempos de toma de muestra del estudio farmacocinético y no se descartan modificaciones en la eliminación por la administración en dosis múltiples. De las interacciones farmacológicas entre cannabidiol con otros fármacos antiepilépticos referenciadas hasta el momento, aquella con clobazam es la que presenta mayor evidencia científica. Los eventos adversos más frecuentes asociados al uso de cannabidiol fueron de gravedad leve o moderada e incluyeron somnolencia, principalmente por el uso conjunto de clobazam, y alteraciones gastrointestinales. Se evidenciaron asimismo anormalidades en la función hepática concomitantes con el uso de ácido valproico.Conclusiones: Ante la creciente demanda de la utilización de cannabidiol en epilepsias refractarias, es fundamental el conocimiento de su farmacología por parte del equipo de salud. En especial, el farmacéutico clínico juega un papel primordial en la monitorización de su seguridad y eficacia. Esto permite la optimización del tratamiento clínico del cannabidiol administrado conjuntamente con otros fármacos antiepilépticos de mayor uso, lo que conduce a maximizar la actividad farmacológica y minimizar la aparición de eventos adversos al igual que de interacciones farmacológicas. El seguimiento clínico del paciente resulta fundamental para evitar la discontinuación del tratamiento o exacerbación de eventos adversos que afecten la calidad de vida del paciente.

Objective Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are immune-mediated diseases characterized by an extensive loss of the epidermal skin layer, often resulting in death. SJS and TEN are often triggered by certain drugs, including antiepileptic drugs (AEDs). Epilepsy is very difficult to treat and often involves the combination of two or more AEDs. In this study, we quantified not only the risk of SJS or TEN associated with single-AED therapy but also the risk related to concomitant AED treatment using reporting-derived signals. Methods An analysis of the Japanese Adverse Drug Event Report (JADER) database was performed from the first quarter of 2004 to the fourth quarter of 2018. The single-AED signals were evaluated using the proportional reporting ratio (PRR), and the combination therapy signals were evaluated using Ω shrinkage measure and combination risk ratio (CRR). Results SJS signals were associated with 11 AEDs, and TEN signals were related to 12 AEDs. Moreover, the following AED combinations were associated with SJS signals: carbamazepine-lorazepam (Ω025 : 0.33, CRR: 2.18) and fosphenytoin-lorazepam (Ω025 : 0.99, CRR: 39.20). The TEN signals were related to the following combinations: clobazam-gabapentin (Ω025 : 0.35, CRR: 3.14), phenytoin-gabapentin (Ω025 : 0.03, CRR: 2.18), valproic acid-gabapentin (Ω025 : 0.15, CRR: 2.25), clobazam-clonazepam (Ω025 : 0.03, CRR: 2.93), clobazam-valproic acid (Ω025 : 0.29, CRR: 1.55), fosphenytoin-lamotrigine (Ω025 : 0.05, CRR: 7.37), and lacosamide-levetiracetam (Ω025 : 0.74, CRR: 1.85). Significance This study identified two AED combinations that increased the SJS signals and seven combinations that increased the TEN signals. Although AED monotherapies require attention for SJS and TEN, some AED combinations require extra caution.

We investigated the effects of cannabidiol (CBD; 21‐day maintenance dose) on the pharmacokinetics (PK) of clobazam (CLB) and monitored the safety of CBD (or placebo) plus CLB in 20 patients with uncontrolled epilepsy on stable doses of CLB. Blood samples collected until 24 hours postdose were evaluated by liquid chromatography tandem mass spectrometry. PK parameters of CLB and major metabolite N‐desmethylclobazam (N‐CLB), valproic acid, stiripentol, levetiracetam, topiramate, plant‐derived highly purified CBD (Epidiolex in the United States; 100 mg/mL oral solution) and its major metabolites were derived using noncompartmental analysis. There was no evidence of a drug‐drug interaction (DDI) between CBD and CLB: geometric mean ratio (GMR) of day 33:day 1 CLB was 1.0 (90%CI, 0.8‐1.2) for Cmax and 1.1 (90%CI, 0.9‐1.2) for AUCtau. There was a significant DDI between CBD and N‐CLB: the GMR of day 33:day 1 N‐CLB was 2.2 (90%CI, 1.4‐3.5) for Cmax and 2.6 (90%CI, 2.0‐3.6) for AUCtau. Placebo had no effect on CLB or N‐CLB; CBD had no effect on levetiracetam. Data were insufficient regarding DDIs with other antiepileptic drugs. The safety profile of CBD (20 mg/kg/day) with CLB was acceptable; all but 1 adverse events (AEs) were mild or moderate. One serious AE (seizure cluster) led to CBD discontinuation. One patient withdrew after intolerable AEs. Although there was no evidence of a CBD and CLB DDI, there was a significant DDI between CBD and N‐CLB. The safety profile of GW Pharmaceuticals’ CBD formulation with CLB was consistent with other GW‐sponsored trials.

Cannabinoid oils are being increasingly used to treat Dravet syndrome, yet the long-term costs and outcomes of this approach are unknown. Thus, we examined the cost effectiveness of cannabinoid oil as an adjunctive treatment (added to clobazam and valproate), compared with adjunctive stiripentol or with clobazam and valproate alone, for the treatment of Dravet syndrome in children. We performed a probabilistic cost-utility analysis from the perspective of the Canadian public health care system, comparing cannabinoid oil and stiripentol (both on a background of clobazam and valproate) with clobazam and valproate alone. Costs and quality-adjusted life-years (QALYs) were estimated using a Markov model that followed a cohort of children aged from 5 to 18 years through model states related to seizure frequency. Model inputs were obtained from the literature. The cost effectiveness of adjunctive cannabinoid oil, adjunctive stiripentol, and clobazam/valproate alone was assessed through sequential analysis. The influence of perspective and other assumptions were explored in scenario analyses. All costs are expressed in 2019 Canadian dollars, and costs and QALYs were discounted at a rate of 1.5% per year. The incremental cost per QALY gained with the use of adjunctive cannabinoid oil, from the health care system perspective, was $32,399 compared with clobazam and valproate. Stiripentol was dominated by cannabinoid oil, producing fewer QALYs at higher costs. At a willingness-to-pay threshold of $50,000, cannabinoid oil was the optimal treatment in 76% of replications. From a societal perspective, cannabinoid oil dominated stiripentol and clobazam/valproate. The interpretation of the results was insensitive to model and input assumptions. Compared with clobazam/valproate, adjunctive cannabinoid oil may be a cost-effective treatment for Dravet syndrome, if a decision maker is willing to pay at least $32,399 for each QALY gained. The opportunity costs of continuing to fund stiripentol, but not cannabinoid oil, should be considered.

We describe an 11-year-old female who presented with severe hypersomnolence after receiving 1 week of modest doses of clobazam (CLB). In reviewing the above case, we considered that the hypersomnolence could be related to a pharmacodynamic, pharmacokinetic, or pharmacogenomic issue associated with CLB or to a combination of these factors. Although serum concentrations of CLB and its active metabolite are sensitive to factors that affect cytochrome-dependent metabolism, drug-drug interactions were omitted as a cause of the hypersomnolence. Subsequent DNA analysis of the cytochrome P450 2C19 gene revealed the patient as *2/*2 genotype with poor metabolizer enzyme activity. Because genetic testing of all patients treated with CLB is currently not practical, CLB dose/concentration ratios and pharmacokinetic drug-drug interaction impact models may be indicated. Genetic testing should be considered when an adverse effect suggests the possibility of a polymorphism important to drug metabolism.

Hot water epilepsy (HWE) is a subtype of reflex epilepsy in which seizures are triggered by the head being immersed in hot water. Hot water or bathing epilepsy is the type of reflex epilepsy most frequently encountered in our clinic. We describe our patients with HWE and also discuss the clinical features, therapeutic approaches, and prognosis. Eleven patients (10 boys, 1 girl), aged 12 months to 13 years, admitted to the pediatric neurology clinic between January 2018 and August 2019, and diagnosed with HWE or bathing epilepsy based on International League Against Epilepsy (ILAE)-2017, were followed up prospectively for similar to 18 months. Patients' clinical and electroencephalography (EEG) findings and treatment details were noted. All 11 patients' seizures were triggered by hot water. Age at first seizure was between 2 months and 12 years. Seizure types were generalized motor seizures, absence, and atonic. EEG was normal in two patients, but nine patients had epileptiform discharges. Magnetic resonance imaging of the brain was performed and reported as normal (except in one case). Histories of prematurity were present in two patients, unprovoked seizures in one, and low birth weight and depressed birth in the other. Patients with HWE have normal neuromuscular development and neurological examination results, together with prophylaxis or seizure control with a single antiepileptic drug, suggesting that it is a self-limited reflex epilepsy. WOS:000571792200003 2-s2.0-85091574351 PubMed: 32294767

Yeni, S. Naz/0000-0001-7372-5430 WOS:000521935300002 Objective: Patients with drug-resistant focal or generalized epilepsy are important in terms of treatment and polytherapy necessity, adverse effect profiles of drugs, and seizure control difficulties. Clobazam (CLB), which has a lesser sedative effect than other benzodiazepines, is frequently used in different countries. In this study, we aimed to present the results related to the demographic characteristics, adverse effects, and treatment efficacy of patients under CLB treatment. Materials and Methods: Patients who were followed up in the outpatient clinic of Cerrahpasa Medical Faculty were screened retrospectively. Sex, age of seizure onset, duration of epilepsy, seizure type, duration of drug use, frequency of seizures before and after CLB, and drug adverse effects were investigated. The decrease in seizure frequency could not be quantitatively evaluated in some patients because the study was retrospective. For this reason, two groups were identified as having a significant reduction in seizure frequency and being seizure-free according to the information provided by the parents and the recorded data. Results: Forty-one patients with CLB who were followed in the epilepsy clinic were examined. The mean age of 26 male and 15 female patients was 30.30 years. The mean duration of epilepsy was 20.4 years. It was determined that 16 patients were either seizure-free or had intervening rare, mild seizures. There was a significant decrease in seizure frequency in nine patients. Headache was observed in one patient, and sedation and dizziness in two patients. Conclusion: CLB is especially recommended for add-on therapy in Lennox-Gastaut syndrome. In this study, it was observed that in focal/generalized, idiopathic/ cryptogenic different groups, 39% of the patients were seizure-free. However, this effect was not lost during the mean follow-up period of 12.2 months. Although the value of this data decreases due to its retrospective nature, the place of CLB in the treatment of focal/generalized epilepsy is important.

Cannabidiol (CBD) is one of the prominent phytocannabinoids found in Cannabis sativa, differentiating from Δ9-tetrahydrocannabinol (THC) for its non-intoxicating profile and its antianxiety/antipsychotic effects. CBD is a multi-target drug whose anti-convulsant properties are supposed to be independent of endocannabinoid receptor CB1 and might be related to several underlying mechanisms, such as antagonism on the orphan GPR55 receptor, regulation of adenosine tone, activation of 5HT1A receptors and modulation of calcium intracellular levels. CBD is a lipophilic compound with low oral bioavailability (6%) due to poor intestinal absorption and high first-pass metabolism. Its exposure parameters are greatly influenced by feeding status (ie, high fat-containing meals). It is mainly metabolized by cytochrome P 450 (CYP) 3A4 and 2C19, which it strongly inhibits. A proprietary formulation of highly purified, plant-derived CBD has been recently licensed as an adjunctive treatment for Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), while it is being currently investigated in tuberous sclerosis complex. The regulatory agencies' approval was granted based on four pivotal double-blind, placebo-controlled, randomized clinical trials (RCTs) on overall 154 DS patients and 396 LGS ones, receiving CBD 10 or 20 mg/kg/day BID as active treatment. The primary endpoint (reduction in monthly seizure frequency) was met by both CBD doses. Most patients reported adverse events (AEs), generally from mild to moderate and transient, which mainly consisted of somnolence, sedation, decreased appetite, diarrhea and elevation in aminotransferase levels, the last being documented only in subjects on concomitant valproate therapy. The interaction between CBD and clobazam, likely due to CYP2C19 inhibition, might contribute to some AEs, especially somnolence, but also to CBD clinical effectiveness. Cannabidivarin (CBDV), the propyl analogue of CBD, showed anti-convulsant properties in pre-clinical studies, but a plant-derived, purified proprietary formulation of CBDV recently failed the Phase II RCT in patients with uncontrolled focal seizures.

Ictal bradyarrhythmia can be challenging to diagnose when motor features of seizures are absent. Associated bradycardia can involve periods of asystole requiring cardiac pacemaker placement. Here, we report a 2-year-old male with a brainstem embryonal tumor with more than 30 seizures per day manifesting as bradycardia, loss of tone, and decreased responsiveness, followed by vomiting. Associated electrographic changes were localized to the right temporal head region, where the patient's tumor exerted mass effect. The patient was treated with lacosamide at higher doses than previously reported (24 mg/kg/d) and became seizure-free on a combination of this medication with clobazam. Oral albuterol was also used to augment his heart rate as the patient was not a candidate for cardiac pacemaker insertion.

The study objective was to determine the relevance of methods to detect clobazam poisoning during the forensic and chemical toxicological examination. The lack of a systematic approach to clobazam identification and assay as a part of forensic chemical and chemical toxicological analyses was demonstrated. The published data on the study of clobazam in biological objects are inconsistent and incomplete, precluding the conduction of focused forensic chemical and toxicological investigations on biological objects with required validity. Various methods of forensic chemical and toxicological investigation of clobazam in biological objects were studied and presented. Data are presented on various physicochemical test methods (TLC, HPLC, UV spectrometry, GC, and GC-MS) for clobazam detection.Определить актуальность методов установления фактов отравления клобазамом при проведении судебно-химического и химико-токсикологического исследований. Установлено отсутствие систематического подхода к идентификации и количественному определению клобазама как объекта исследования при судебно-химическом и химико-токсикологическом анализах. При анализе данных литературы по исследованию клобазама в биологических объектах показано, что они имеют разрозненный и неполный характер, что не позволяет проводить данные исследования на современном уровне. Изучены и представлены различные методы судебно-химического и химико-токсикологического исследований клобазама в биологических объектах. Приведены данные по использованию различных физико-химических методов анализа (ТСХ, ВЭЖХ, УФ-спектрометрия, ГХ и ГХ-МС) при исследовании на наличие клобазама.

The management of refractory epilepsy involves treatment with more than one antiseizure medication (ASM). Combination of ASMs with distinct mechanisms of action are hypothesized to improve overall treatment effectiveness. In clinical trials, concomitant use of cannabidiol (CBD) and clobazam (CLB) was associated with increased seizure reduction and bidirectional elevation in levels of their active metabolites, 7-hydroxy-cannabidiol (7-OH-CBD) and nor-clobazam (n-CLB). Using isobolographic analysis, we investigated whether CBD and CLB interacted pharmacodynamically. In the mouse maximal electroshock seizure (MES) test, brain tissue levels of CBD and CLB corresponding to seizure prevention in 50% of animals (brain Effective Exposure, bEE

Antiseizure medications (ASMs) are the mainstay for the treatment of seizure disorders. However, about one-third of people with epilepsy remain refractory to current ASMs. Cannabidiol (CBD) has recently been approved as ASM for three refractory epilepsy syndrome indications in children and adults. In this study, we evaluated the overall clinical potential of an oral CBD to treat refractory epilepsy in patients with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC) through a systematic review and meta-analysis. A comprehensive search of databases was conducted, including randomized controlled trials (RCTs) assessing the effect of CBD in epilepsy patients. The review was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The review focused on RCTs involving patients receiving highly purified oral CBD (Epidiolex, 10 to 50 mg/kg/day) for up to 16 weeks. A subgroup analysis by syndrome and CBD with or without concomitant clobazam was conducted. The key outcomes were reduction in seizure frequency, differences in 50% responder rates, adverse events, and interactions with clobazam as co-therapy. Odds ratio (OR) with 95% confidence interval (CI) were estimated. Of 1183 articles screened, we included 6 RCTs meeting our eligibility criteria. All studies were considered to have a low risk of bias. In the pooled analysis, CBD treatment was found to be more efficacious compared to placebo (OR = 2.45, 95% CI =1.81-3.32, p 0.01). Subgroup analysis by syndrome demonstrated the odds of ≥50% reduction in seizures with CBD treatment in patients with DS (OR = 2.26, 95% CI:1.38-3.70), LGS (OR = 2.98, 95% CI:1.83-4.85) and TSC (OR = 1.99, 95% CI = 1.06-3.76). Compared with placebo, CBD was associated with increased adverse events (OR = 1.81, 95% CI = 1.33-2.46) such as diarrhea, somnolence, and sedation, and any serious adverse events (OR = 2.86, 95% CI = 1.63-5.05). Other factors, including dosage and clobazam co-therapy, were significantly associated with a greater effect on seizure control and side effects of CBD. In conclusion, the study shows that CBD is highly efficacious both as standalone and adjunct therapy with clobazam for controlling seizures in DS, LGS, and TSC conditions while limiting side effects. Further pharmacodynamic investigation of CBD actions, drug interaction assessments, and therapeutic management guidelines are warranted.

With this study, we aim to test the hypothesis that the effect of cannabidiol on drop-seizure frequency in patients with Lennox-Gastaut syndrome and Dravet syndrome could be attributed to a drug-drug interaction with clobazam. We performed clinical trial simulations for the effect of 20 mg/kg/day cannabidiol on drop-seizure frequency in patients with Lennox-Gastaut syndrome. We assumed that patients taking 10 or 20 mg clobazam would have a 2- to 7-fold increase in N-desmethylclobazam exposure, whereas patients not taking clobazam would have a median reduction in drop-seizure frequency and a variability in the percent reduction similar to the placebo group. The results show that the effect of cannabidiol on the median reduction in drop-seizure frequency in patients with Lennox-Gastaut syndrome may be explained by a drug-drug interaction with clobazam. This may have important implications for the use of cannabidiol and its Food and Drug Administration registration.

Eating epilepsy is a rare form of reflex epilepsy where seizures are triggered by eating. We describe a case series of 12 such patients presenting to our epilepsy clinic based in North India. Eating epilepsy was noted to have male predominance with focal seizures with impaired awareness. Most of these patients had either temporal or perisylvian localization. Clobazam taken half an hour before meal was found to be an effective add-on therapy in its management.