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1.
Drugs Today (Barc) ; 57(7): 449-454, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34268532

RESUMO

Fenfluramine hydrochloride, initially utilized as a weight loss drug in the 1970s and later removed from the market for adverse cardiopulmonary side effects, has since been repurposed as an antiseizure medicine (ASM). The potential antiseizure effects of fenfluramine were first identified in patients with photosensitive epilepsy in the 1980s but it was not rigorously explored as a treatment option until 30 years later. Compared with other ASMs, fenfluramine offers a novel mechanism by acting on serotonin and σ1 receptors, demonstrated in vitro and in vivo in animal models of Dravet syndrome. Results from a large double-blind, placebo-controlled trial demonstrated robust efficacy for seizure reduction in patients with Dravet syndrome, and met its primary endpoint with the 0.7 mg/kg/day fenfluramine treatment group experiencing a 62.3% or greater reduction in mean monthly convulsive seizure frequency (MCSF) compared with placebo. Here we provide a comprehensive review of the preclinical and clinical activity of fenfluramine, a recently approved drug for treatment of epilepsy in patients with Dravet syndrome.


Assuntos
Epilepsias Mioclônicas , Espasmos Infantis , Animais , Anticonvulsivantes/uso terapêutico , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/genética , Fenfluramina/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Convulsões/tratamento farmacológico , Espasmos Infantis/tratamento farmacológico
2.
Epilepsy Behav ; 121(Pt A): 108024, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34023810

RESUMO

OBJECTIVE: Individuals with Dravet syndrome (DS) experience frequent pharmacoresistant seizures beginning in infancy. Most exhibit poor neurodevelopmental outcomes including motor function difficulties, behavior problems, and cognitive impairment. Cognitive deficits in children with DS have been associated with seizure frequency and antiseizure medication (ASM) use. Recent research in children and young adults with DS has begun to examine the role of executive functions (EFs), as these include higher-order cognitive functions and may mediate the relationship between risk factors and cognitive impairment. Current conceptualizations, however, of EFs involve the broader self-regulation of cognitive, behavioral, and emotional domains. We explored relationships between reduction in convulsive seizure frequency and everyday EFs in a subset of children and young adults with DS treated with adjunctive fenfluramine for 1 year. METHODS: This is a post-hoc analysis of data from children and young adults with Dravet syndrome aged 5-18 years who participated in a phase 3 randomized, placebo-controlled clinical trial (core study) followed by completion of at least 1 year of fenfluramine treatment in an open-label extension (OLE) study. Eligible children and young adults started the OLE study at 0.2 mg/kg/day fenfluramine and were titrated to optimal seizure control and tolerability (maximum daily dose: 26 mg/day). Parents/caregivers documented convulsive seizure frequency per 28 days (i.e., monthly convulsive seizure frequency [MCSF]) by electronic diary. A parent/caregiver for each child also completed the Behavior Rating Inventory of Executive Function (BRIEF®) parent form, a questionnaire capturing parents'/caregivers' perceptions of everyday EF that was included as a safety measure to assess treatment-related adverse effects on EF during the trial. Ratings on BRIEF® were mapped to the current edition, the BRIEF®2 parent form, and were used to calculate T-scores for the Behavior Regulation Index (BRI), Emotion Regulation Index (ERI), Cognitive Regulation Index (CRI), and Global Executive Composite (GEC). Change in BRIEF®2 T-scores from baseline in the core study to Year 1 of the OLE study was calculated. Spearman's rho correlation coefficients assessed associations between change in BRIEF®2 indexes/composite T-scores and percentage change in MCSF. Children and young adults were divided into 2 groups based on percentage of MCSF reduction achieved from pre-randomization baseline in the core study to Year 1 of the OLE study: <50% and ≥50% MCSF reduction. Changes in the distribution of BRIEF®2 indexes/composite T-scores were compared between MCSF reduction groups using Mann-Whitney U tests. The proportions of children and young adults in these groups who showed clinically meaningful improvement in everyday EF, defined as Reliable Change Index (RCI) values ≥95% certainty relative to a reference population of neurotypically developing healthy volunteers, were then assessed by cross-tabulations and Somers' D tests (p ≤ 0.05). When there was a significant meaningful improvement in an index score, post-hoc analyses using the same statistical methods were conducted to evaluate the individual BRIEF®2 scales composing that index. Supplemental analyses examined the proportions of patients in MCSF reduction groups <25% and ≥75% who achieved clinically meaningful improvement or worsening in everyday EF using RCI values ≥95% certainty and ≥80% certainty, respectively, relative to the reference population. RESULTS: At the time of analysis, 58 children and young adults (mean age: 11 ±â€¯4 years) had reached OLE Year 1 of fenfluramine treatment with a 75% median percentage reduction in seizure frequency from pre-randomization baseline. Overall, there was a significant correlation between change in MCSF and change in BRIEF®2 T-scores for ERI (p = 0.008), but not for BRI, CRI, or GEC (p > 0.05). At OLE Year 1, 78% (n = 45) of total children/young adults had ≥50% MCSF reduction (50% [n = 29] achieved ≥75% MCSF reduction) and 22% (n = 13) of total children/young adults had <50% MCSF reduction (12% [n = 7] showed <25% MCSF reduction). The ≥50% MCSF reduction group was significantly more likely to achieve clinically meaningful improvement (RCI ≥ 95% certainty) in ERI (p = 0.002) and in CRI (p = 0.001) than the <50% MCSF reduction group. There were no significant differences in the proportions of children and young adults in the 2 MCSF reduction groups showing clinically meaningful worsening (RCI ≥ 80% certainty) on the BRIEF®2 indexes/composite. SIGNIFICANCE: In children and young adults with DS, the magnitude of reduction in MCSF after long-term treatment with adjunctive fenfluramine was associated with clinically meaningful levels of improvement in everyday EF. Seventy-eight percent (78%) of children and young adults treated with adjunctive fenfluramine for 1 year in the OLE study achieved ≥50% reduction in MCSF, for a magnitude of efficacy associated with a significantly greater likelihood of experiencing clinically meaningful improvement in emotion regulation and cognitive regulation.


Assuntos
Epilepsias Mioclônicas , Função Executiva , Adolescente , Anticonvulsivantes/uso terapêutico , Criança , Epilepsias Mioclônicas/tratamento farmacológico , Fenfluramina/uso terapêutico , Humanos , Convulsões/tratamento farmacológico , Adulto Jovem
4.
Eur J Paediatr Neurol ; 31: 10-14, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33540241

RESUMO

OBJECTIVE: Clinical trials typically report antiepileptic drug efficacy by evaluating reduction in monthly convulsive seizure frequency (MCSF) through group response (active versus placebo). Although useful for regulatory purposes, population statistics do not easily translate into clinical practice, where treatment decisions are made on an individual-patient basis. Responder analyses help bridge this gap by showing proportions of patients who achieved various MCSF improvement levels. Deriving numbers needed to treat (NNTs) to achieve clinically desirable response levels can further inform individual decision-making. We calculated the NNT with fenfluramine to achieve "clinically meaningful" (≥50%) or "profound" (≥75%) MCSF reductions in patients with Dravet syndrome (DS). METHODS: NNT to achieve ≥50% or ≥75% MCSF reduction was assessed using longitudinal data from two phase 3 studies for adjunctive fenfluramine in DS patients aged 2-18 years. NNT was calculated: 1/((Experimental-Responder Rate)-(Control-Responder Rate)). RESULTS: In Study 1, NNTs to achieve ≥50% and ≥75% MCSF reduction were 1.8 and 2.1 at 0.7 mg/kg/day fenfluramine. In Study 2, these NNTs were 2.0 and 3.1, respectively. These results were seen as early as Weeks 6-7 and were sustained through Weeks 14-15. INTERPRETATION: For every two to three patients with DS treated with fenfluramine in these trials, one patient achieved ≥50% or ≥75% MCSF reduction, respectively, compared with placebo (large treatment effect size; Cohen's d≈0.8). Responder analyses and NNTs can aid in clinical decision-making by offering clinically important information that is complementary to the population mean data on the chance of an individual patient achieving meaningful levels of MCSF improvement. (NCT02682927/NCT02826863, NCT02926898).


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsias Mioclônicas/tratamento farmacológico , Fenfluramina/uso terapêutico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Números Necessários para Tratar , Resultado do Tratamento
5.
Seizure ; 85: 119-126, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33461030

RESUMO

BACKGROUND: Dravet syndrome (DS) is an infantile-onset developmental and epileptic encephalopathy syndrome with limited treatment options. We aimed to evaluate the efficacy and tolerability of fenfluramine in patients with Dravet syndrome using meta-analytical techniques. METHODS: We searched for relevant randomized controlled trials and non-randomized studies involving children with Dravet syndrome on fenfluramine therapy in MEDLINE, CENTRAL, EMBASE, Google Scholar and Web of Science database (31 July 2020). The primary outcome for the efficacy of fenfluramine was reduction in monthly convulsive seizure frequency. We carried out a random effect meta-analysis focusing on efficacy and safety variables. Only Randomized Controlled Trials (RCT) were included in the meta-analysis. The risk of bias was assessed for each study, and GRADE was used to assess the quality of evidence for each outcome. RESULTS: Of 61 publications initially screened, 12 were reviewed as full-text. Seven articles including 2 RCTs, 4 uncontrolled studies (3 prospective and one retrospective study), and one case report described responses to fenfluramine in 144 DS patients (54 % male, mean age of 8.8 years, median dose of 0.4 mg/kg/day). Fenfluramine was found to be more efficacious than placebo, in terms of mean convulsive and total seizure frequency reduction (mean difference: -45.3 % (95 % CI: -48.1 %, -42.4 %, p < 0.00001) and -39.7 % (-46.7 %, -32.7 %, p < 0.00001)). A greater proportion of patients in the fenfluramine arm achieved >25 %, >50 %, >75 % and 100 % seizure reductions (odds ratios: 6.5 (3.7, 11.5, p < 0.00001), 10.6 (5.3, 21.3, p < 0.00001), 22.7(6.9, 75.3, p < 0.00001) and 9.3(1.7, 51.4, p = 0.01) respectively). The incidence of serious adverse events was not greater in the fenfluramine groups (OR: 1.02 (0.5, 2.19, p = 0.96)). CONCLUSION: Fenfluramine appears to be a safe and efficacious antiseizure medication in patients with Dravet syndrome.


Assuntos
Epilepsias Mioclônicas , Espasmos Infantis , Criança , Epilepsias Mioclônicas/tratamento farmacológico , Feminino , Fenfluramina/uso terapêutico , Humanos , Lactente , Masculino , Convulsões/tratamento farmacológico , Resultado do Tratamento
6.
Acta Neurol Scand ; 143(4): 339-348, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33336426

RESUMO

BACKGROUND: Dravet syndrome (DS) is a severe, drug-resistant, developmental epileptic encephalopathy. Despite multiple anti-epileptic drug regimens, the syndrome remains poorly controlled and nearly half of patients still experience at least four tonic-clonic seizure per month. Recently, several clinical trials demonstrated that fenfluramine may provide a significant reduction in convulsive seizure frequency in the treatment of Dravet syndrome. METHODS: A computerized literature search of Web of Science, MEDLINE (Ovid and PubMed), Cochrane Library, EMBASE, and Google Scholar was performed from inception until December 31, 2019. We included randomized placebo-controlled trials for the treatment of Dravet syndrome. We calculated the risk ratio (RR) of ≥50% and 100% reduction seizure frequency from baseline, along with the treatment-related withdrawals and serious adverse events, using the fixed-effect model. Quality assessment of included studies was performed with the Cochrane Collaboration's tool. KEY RESULTS: Two trials with a total of 206 patients were included. The pooled RR of 5.49 (95% CI 3.13-9.65) showed that a significantly greater proportion in the fenfluramine group achieved ≥50% reduction in monthly convulsive seizure frequency (MCSF). As for the complete seizure free rate, the pooled RR of 5.75 (95% CI 1.03-32.07) also demonstrated the favorable efficacy of fenfluramine, even though the difference was not statistically significant (p = 0.046). However, a significantly greater proportion of patients in the fenfluramine group experienced no more than one seizure during the treatment period (RR 13.82, 95% CI 2.68-71.27, p = 0.002). There were no significant differences in withdrawals and serious adverse events between the two treatment groups. No valvular heart disease or pulmonary arterial hypertension was observed in participants. The most common adverse events reported by included trials were diarrhea, fatigue, lethargy, nasopharyngitis, pyrexia, seizure, decreased appetite, and weight loss. CONCLUSIONS: Fenfluramine is an effective antiepileptic drug for pediatric patients with Dravet syndrome, demonstrating clinically meaningful reduction in convulsive frequency, and generally could be well tolerated.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/tratamento farmacológico , Fenfluramina/uso terapêutico , Anticonvulsivantes/efeitos adversos , Criança , Pré-Escolar , Fadiga/induzido quimicamente , Fenfluramina/efeitos adversos , Febre/induzido quimicamente , Humanos , Estudos Multicêntricos como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Convulsões/tratamento farmacológico
8.
Epilepsia ; 61(11): 2396-2404, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33078386

RESUMO

OBJECTIVE: Fenfluramine has been shown to provide clinically meaningful and statistically significant reductions in convulsive seizure frequency in children and adolescents (aged 2-18 years) with Dravet syndrome in two randomized, placebo-controlled clinical trials. The objective of this analysis was to assess longer-term safety and efficacy of fenfluramine in patients who completed one of the double-blind studies and entered an open-label extension (OLE) study. METHODS: Patients enrolling in the OLE study initiated fenfluramine at 0.2 mg/kg/d regardless of their treatment assignment in the double-blind study. After 4 weeks, the fenfluramine dose could be titrated based on efficacy and tolerability to maximum of 0.7 mg/kg/d (absolute maximum 27 mg/d) or maximum of 0.4 mg/kg/d (absolute maximum 17 mg/d) in patients receiving concomitant stiripentol. The number and type of seizures were recorded daily in an electronic diary, and safety, including echocardiography, was assessed at Months 1, 2, and 3, and at 3-month intervals thereafter. RESULTS: A total of 232 patients were enrolled as of March 13, 2018. During this analysis period, patients were treated for a median 256 days (range = 46-634 days). Over the entire OLE analysis period, the median decrease in convulsive seizure frequency compared to baseline in the double-blind studies was -66.8% (range = -100% to 234.9%; P < .001). The median reduction in seizure frequency was similar in patients <6 (-75.7%) and ≥6 years old (-64.7%). The most commonly reported adverse events included pyrexia (21.6%), nasopharyngitis (19.4%), and decreased appetite (-15.9%). No valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) was observed. SIGNIFICANCE: Study results demonstrate that fenfluramine provides clinically meaningful (≥50%) seizure frequency reduction over an extended period in patients with Dravet syndrome. No patient developed VHD or PAH, and fenfluramine was generally well tolerated.


Assuntos
Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/tratamento farmacológico , Fenfluramina/administração & dosagem , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Inibidores de Captação de Serotonina/administração & dosagem , Adolescente , Criança , Pré-Escolar , Método Duplo-Cego , Epilepsias Mioclônicas/epidemiologia , Feminino , Fenfluramina/efeitos adversos , Febre/induzido quimicamente , Humanos , Estudos Longitudinais , Masculino , Convulsões/epidemiologia , Inibidores de Captação de Serotonina/efeitos adversos , Resultado do Tratamento , Adulto Jovem
9.
Epilepsia ; 61(11): 2405-2414, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32945537

RESUMO

OBJECTIVE: Dravet syndrome (DS) is a drug-resistant, infantile onset epilepsy syndrome with multiple seizure types and developmental delay. In recently published randomized controlled trials, fenfluramine (FFA) proved to be safe and effective in DS. METHODS: DS patients were treated with FFA in the Zogenix Early Access Program at four Italian pediatric epilepsy centers. FFA was administered as add-on, twice daily at an initial dose of 0.2 mg/kg/d up to 0.7 mg/kg/d. Seizures were recorded in a diary. Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6 months. RESULTS: Fifty-two patients were enrolled, with a median age of 8.6 years (interquartile range [IQR] = 4.1-13.9). Forty-five (86.5%) patients completed the efficacy analysis. The median follow-up was 9.0 months (IQR = 3.2-9.5). At last follow-up visit, there was a 77.4% median reduction in convulsive seizures. Thirty-two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure-free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA. SIGNIFICANCE: In this real-world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated.


Assuntos
Epilepsias Mioclônicas/tratamento farmacológico , Fenfluramina/administração & dosagem , Convulsões/tratamento farmacológico , Inibidores de Captação de Serotonina/administração & dosagem , Adolescente , Adulto , Anorexia/induzido quimicamente , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Criança , Pré-Escolar , Epilepsias Mioclônicas/diagnóstico por imagem , Epilepsias Mioclônicas/fisiopatologia , Feminino , Fenfluramina/efeitos adversos , Seguimentos , Humanos , Masculino , Estudos Prospectivos , Convulsões/diagnóstico por imagem , Convulsões/fisiopatologia , Inibidores de Captação de Serotonina/efeitos adversos , Resultado do Tratamento , Adulto Jovem
10.
Epilepsia ; 61(11): 2386-2395, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32809271

RESUMO

OBJECTIVE: Fenfluramine, which was previously approved as a weight loss drug, was withdrawn in 1997 when reports of cardiac valvulopathy emerged. The present study was conducted in part to characterize the cardiovascular safety profile of low-dose fenfluramine when used in a pediatric population to reduce seizure frequency in patients with Dravet syndrome. METHODS: Patients 2- to 18-years-old with Dravet syndrome who had completed any of three randomized, placebo-controlled clinical trials of fenfluramine were offered enrollment in this open-label extension (OLE) study. All patients were treated with fenfluramine starting at a dose of 0.2 mg/kg/day (oral solution dosed twice per day), which was titrated to maximal effect with a dose limit of 0.7 mg/kg/day (maximum 26 mg/day) or 0.4 mg/kg/day (maximum 17 mg/day) in patients receiving concomitant stiripentol. Standardized echocardiographic examinations were conducted at Week 4 or 6 and then every 3 months during the OLE study to monitor cardiac valve function and structure and pulmonary artery pressure. The primary end point for the echocardiography analysis was the number of patients who developed valvular heart disease or pulmonary artery hypertension (PAH) during treatment. RESULTS: A total of 232 patients were enrolled in the study. The average age of patients was 9.1 ± 4.7 years, and 55.2% were male. The median duration of treatment with fenfluramine was 256 days (range = 58-634 days), and the mean dose of fenfluramine was 0.41 mg/kg/day. No cases of valvular heart disease or PAH were observed. SIGNIFICANCE: Longitudinal echocardiography over a median 8.4 months of treatment with fenfluramine suggests a low risk of developing cardiac valvulopathy and PAH when used to treat pediatric patients with Dravet syndrome.


Assuntos
Eletrocardiografia/efeitos dos fármacos , Epilepsias Mioclônicas/diagnóstico por imagem , Epilepsias Mioclônicas/tratamento farmacológico , Fenfluramina/administração & dosagem , Doenças das Valvas Cardíacas/diagnóstico por imagem , Inibidores de Captação de Serotonina/administração & dosagem , Adolescente , Criança , Pré-Escolar , Método Duplo-Cego , Eletrocardiografia/métodos , Feminino , Fenfluramina/efeitos adversos , Doenças das Valvas Cardíacas/induzido quimicamente , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos , Inibidores de Captação de Serotonina/efeitos adversos , Resultado do Tratamento , Adulto Jovem
11.
Physiol Behav ; 224: 113029, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32590091

RESUMO

Dopamine, opioid and muscarinic receptor antagonists differentially reduce sucrose and saccharin intakes across inbred mouse strains. Whereas these systems stimulate sweet intake, serotonin signaling inhibits food intake. The present study examined whether fluoxetine (0.1-10 mg/kg) or d-fenfluramine (0.1-6 mg/kg) differentially inhibited sucrose or saccharin intake in BALB/c, C57BL/6 and SWR mice. Fluoxetine marginally altered sucrose intake in all strains. d-fenfluramine significantly, but quite similarly reduced (ID40) sucrose and saccharin intake in BALB/c (5.7 vs. 5.8 mg/kg), C57BL/6 (4.4 vs. 4.3 mg/kg) and SWR (4.6 vs. 5.6 mg/kg) mice, suggesting serotonin-induced inhibition of orosensory mechanisms in all three inbred mouse strains.


Assuntos
Fluoxetina , Antagonistas de Entorpecentes , Animais , Fenfluramina , Fluoxetina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Sacarose
12.
Rev Neurol (Paris) ; 176(6): 444-447, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32409177

RESUMO

There are currently five compounds (clobazam, felbamate, lamotrigine, topiramate, rufinamide) available for prescription with a demonstrated efficacy on drop seizures for Lennox-Gastaut syndrome (LGS). There are also currently new and under-investigation compounds. This paper gives an overview on these novel developments for LGS based on the lecture given at the French Chapter meeting of the International League Against Epilepsy (ILAE) held in Paris in October 2019. Five compounds were discussed. Epidiolex (cannabidiol) has been approved recently based on positive randomized control trials in LGS patients. Four drugs are under investigation according to a search on the 'clinicaltrials.gov' database. Perampanel and fenfluramine are both being studied in ongoing phase 3 studies. Two compounds are in an earlier stage of development with ongoing phase 1 and 2 studies: carisbamate and OV953. We summarized the publicly available data. Based on these drug development programs, we can expect that new compounds will become available for LGS in the next years, possibly resulting in new treatment paradigms.


Assuntos
Anticonvulsivantes/uso terapêutico , Drogas em Investigação/uso terapêutico , Síndrome de Lennox-Gastaut/tratamento farmacológico , Terapias em Estudo/tendências , Canabidiol/uso terapêutico , Desenvolvimento de Medicamentos/tendências , Fenfluramina/uso terapêutico , Humanos , Síndrome de Lennox-Gastaut/epidemiologia , Piridonas/uso terapêutico , Terapias em Estudo/métodos , Triazóis
13.
Pediatr Neurol ; 107: 28-40, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32165031

RESUMO

Dravet syndrome is a debilitating epileptic encephalopathy of childhood with few treatment options available in the United States before 2018. In the modern era, new genetic testing options will allow diagnosis closer to disease onset. Three new medicines-stiripentol, cannabidiol, and fenfluramine-have documented efficacy and safety as adjunctive therapies for treating pharmacoresistant Dravet syndrome. Early diagnosis resulting in earlier treatment with these and other medications may improve prognosis of long-term outcomes, including less severity of cognitive, motor, and behavioral impairments. New rescue medication formulations can now manage acute seizures and help prevent status epilepticus via intranasal, buccal, and intramuscular routes as opposed to rectal administration. Preventing status epilepticus and generalized tonic-clonic seizures could potentially lower the risk of sudden unexpected death in epilepsy. With this changing landscape in diagnostic and treatment options comes questions and controversies for the practicing clinician, especially as diagnostic techniques outpace clinical treatment strategies. Critical decision points include when to start treatment, what pharmacotherapy combinations to try first, which rescue medication to recommend, and how to advise parents on controversial topics (e.g., immunizations). Given that most patients require polypharmacy, clinicians must be cognizant of drug-drug interactions between new medicines, existing anti-epileptic drugs, and other medications to manage comorbidities and must have an understanding of available therapeutic drug monitoring strategies and pharmacokinetic parameters. This review places new diagnostic, treatment and acute care options into the modern era and provides an overview of the challenges and opportunities facing the pediatric epileptologist in this rapidly changing landscape.


Assuntos
Anticonvulsivantes/uso terapêutico , Canabidiol/uso terapêutico , Dioxolanos/uso terapêutico , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/tratamento farmacológico , Fenfluramina/uso terapêutico , Testes Genéticos , Criança , Humanos
14.
Epilepsy Behav ; 105: 106989, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32169824

RESUMO

OBJECTIVE: Adjunctive fenfluramine hydrochloride, classically described as acting pharmacologically through a serotonergic mechanism, has demonstrated a unique and robust clinical response profile with regard to its magnitude, consistency, and durability of effect on seizure activity in patients with pharmacoresistant Dravet syndrome. Recent findings also support long-term improvements in executive functions (behavior, emotion, cognition) in these patients. The observed clinical profile is inconsistent with serotonergic activity alone, as other serotonergic medications have not been demonstrated to have these clinical effects. This study investigated a potential role for σ1 receptor activity in complementing fenfluramine's serotonergic pharmacology. METHODS: Radioligand binding assays tested the affinity of fenfluramine for 47 receptors associated with seizures in the literature, including σ receptors. Cellular function assays tested fenfluramine and norfenfluramine (its major metabolite) activity at various receptors, including adrenergic, muscarinic, and serotonergic receptors. The σ1 receptor activity was assessed by the mouse vas deferens isometric twitch and by an assay of dissociation of the σ1 receptor from the endoplasmic reticulum stress protein binding immunoglobulin protein (BiP). In vivo mouse models assessed fenfluramine activity at σ1 receptors in ameliorating dizocilpine-induced learning deficits in spatial and nonspatial memory tasks, alone or in combination with the reference σ1 receptor agonist PRE-084. RESULTS: Fenfluramine and norfenfluramine bound ≥30% to ß2-adrenergic, muscarinic M1, serotonergic 5-HT1A, and σ receptors, as well as sodium channels, with a Ki between 266 nM (σ receptors) and 17.5 µM (ß-adrenergic receptors). However, only σ1 receptor isometric twitch assays showed a positive functional response, with weak stimulation by fenfluramine and inhibition by norfenfluramine. Fenfluramine, but not the 5-HT2C agonist lorcaserin, showed a positive modulation of the PRE-084-induced dissociation of σ1 protein from BiP. Fenfluramine also showed dose-dependent antiamnesic effects against dizocilpine-induced learning deficits in spontaneous alternation and passive avoidance responses, which are models of σ1 activation. Moreover, low doses of fenfluramine synergistically potentiated the low-dose effect of PRE-084, confirming a positive modulatory effect at the σ1 receptor. Finally, all in vivo effects were blocked by the σ1 receptor antagonist NE-100. SIGNIFICANCE: Fenfluramine demonstrated modulatory activity at σ1 receptors in vitro and in vivo in addition to its known serotonergic activity. These studies identify a possible new σ1 receptor mechanism underpinning fenfluramine's central nervous system effects, which may contribute to its antiseizure activity in Dravet syndrome and positive effects observed on executive functions in clinical studies.


Assuntos
Fenfluramina/metabolismo , Fenfluramina/farmacologia , Receptores sigma/metabolismo , Convulsões/tratamento farmacológico , Convulsões/metabolismo , Animais , Benzazepinas/metabolismo , Benzazepinas/farmacologia , Células CHO , Cricetinae , Cricetulus , Fenfluramina/uso terapêutico , Células HEK293 , Humanos , Masculino , Camundongos , Morfolinas/metabolismo , Morfolinas/farmacologia , Ligação Proteica/fisiologia , Ensaio Radioligante/métodos , Ratos , Receptores sigma/agonistas , Receptores sigma/antagonistas & inibidores
16.
Neuropediatrics ; 51(2): 135-145, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32079034

RESUMO

Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy, is a severe developmental and epileptic encephalopathy caused by loss-of-function mutations in one copy of SCN1A (haploinsufficiency), located on chromosome 2q24, with decreased function of Nav1.1 sodium channels in GABAergic inhibitory interneurons. Pharmacoresistant seizures in DS start in the infancy in the form of hemiclonic febrile status epilepticus. Later, other intractable seizure types develop including myoclonic seizures. Early normal development in infancy evolves into moderate to severe intellectual impairment, motor impairment, behavioral abnormalities, and later a characteristic crouching gait. Clobazam, valproate, levetiracetam, topiramate, zonisamide, ketogenic diet, and vagus nerve stimulation had been shown to be effective, but even with polytherapy, only 10% of patients get adequate seizure control. The author provides a narrative review of the current treatment paradigm as well as recent advances in the management of DS based on a comprehensive literature review (MEDLINE using PubMed and OvidSP vendors with appropriate keywords to incorporate recent evidence), personal practice, and experience. In recent years, the treatment paradigm of DS is changing with the approval of pharmaceutical-grade cannabidiol oil and stiripentol. Another novel antiepileptic drug (AED), fenfluramine, had also shown excellent efficacy in phase 3 studies of DS. However, these AEDs primarily control seizures without addressing the underlying pathogenesis and other important common comorbidities such as cognitive impairment, autistic behavior, neuropsychiatric abnormalities, and motor impairment including crouching gait. Several agents targeted for DS are in the developmental stage: TAK935, lorcaserin, clemizole, huperzine analog, ataluren, selective sodium channel modulators and activators, antisense oligonucleotide therapy, and adenoviral vector therapy. As DS is associated with a high risk of sudden unexpected death in epilepsy, seizure detection devices can be used in this population for testing and clinical validation of these devices.


Assuntos
Anticonvulsivantes/uso terapêutico , Canabidiol/uso terapêutico , Dioxolanos/uso terapêutico , Epilepsias Mioclônicas/terapia , Fenfluramina/uso terapêutico , Terapia Genética , Oligonucleotídeos Antissenso/uso terapêutico , Epilepsias Mioclônicas/tratamento farmacológico , Humanos
17.
Epilepsia ; 61(3): 549-560, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32096222

RESUMO

OBJECTIVE: To pinpoint the earliest cellular defects underlying seizure onset (epileptogenic period) during perinatal brain development in a new zebrafish model of Dravet syndrome (DS) and to investigate potential disease-modifying activity of the 5HT2 receptor agonist fenfluramine. METHODS: We used CRISPR/Cas9 mutagenesis to introduce a missense mutation, designed to perturb ion transport function in all channel isoforms, into scn1lab, the zebrafish orthologue of SCN1A (encoding voltage-gated sodium channel alpha subunit 1). We performed behavioral analysis and electroencephalographic recordings to measure convulsions and epileptiform discharges, followed by single-cell RNA-Seq, morphometric analysis of transgenic reporter-labeled γ-aminobutyric acidergic (GABAergic) neurons, and pharmacological profiling of mutant larvae. RESULTS: Homozygous mutant (scn1labmut/mut ) larvae displayed spontaneous seizures with interictal, preictal, and ictal discharges (mean = 7.5 per 20-minute recording; P < .0001; one-way analysis of variance). Drop-Seq analysis revealed a 2:1 shift in the ratio of glutamatergic to GABAergic neurons in scn1labmut/mut larval brains versus wild type (WT), with dynamic changes in neuronal, glial, and progenitor cell populations. To explore disease pathophysiology further, we quantified dendritic arborization in GABAergic neurons and observed a 40% reduction in arbor number compared to WT (P < .001; n = 15 mutant, n = 16 WT). We postulate that the significant reduction in inhibitory arbors causes an inhibitory to excitatory neurotransmitter imbalance that contributes to seizures and enhanced electrical brain activity in scn1labmut/mut larvae (high-frequency range), with subsequent GABAergic neuronal loss and astrogliosis. Chronic fenfluramine administration completely restored dendritic arbor numbers to normal in scn1labmut/mut larvae, whereas similar treatment with the benzodiazepine diazepam attenuated seizures, but was ineffective in restoring neuronal cytoarchitecture. BrdU labeling revealed cell overproliferation in scn1labmut/mut larval brains that were rescued by fenfluramine but not diazepam. SIGNIFICANCE: Our findings provide novel insights into early mechanisms of DS pathogenesis, describe dynamic cell population changes in the scn1labmut/mut brain, and present first-time evidence for potential disease modification by fenfluramine.


Assuntos
Encéfalo/fisiopatologia , Epilepsias Mioclônicas/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Plasticidade Neuronal/genética , Proteínas de Peixe-Zebra/genética , Animais , Anticonvulsivantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Sistemas CRISPR-Cas , Proliferação de Células/efeitos dos fármacos , Diazepam/farmacologia , Modelos Animais de Doenças , Eletroencefalografia , Epilepsias Mioclônicas/metabolismo , Epilepsias Mioclônicas/patologia , Epilepsias Mioclônicas/fisiopatologia , Fenfluramina/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/patologia , Perfilação da Expressão Gênica , Gliose/genética , Gliose/patologia , Locomoção/efeitos dos fármacos , Mutação de Sentido Incorreto , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , RNA-Seq , Reação em Cadeia da Polimerase em Tempo Real , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Análise de Célula Única , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismo
18.
Pediatr Neurol ; 107: 24-27, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31980296

RESUMO

BACKGROUND: Multiple medications have recently been approved or are nearing US Food and Drug Administration approval for treatment of pediatric epilepsy, while a number of other compounds are in development. Many of these therapies are seeking indications in rare epilepsy syndromes and present novel mechanisms of action for the treatment of epilepsy. METHODS: Data related to drugs in development or under study were accessed following literature search via PubMed or author knowledge of publically available data. RESULTS: Several new compounds are recently approved or under study for epilepsy in children. CONCLUSIONS: The following is a brief overview of the new and emerging medications for the treatment of pediatric epilepsy.


Assuntos
Anticonvulsivantes/uso terapêutico , Canabidiol/uso terapêutico , Dioxolanos/uso terapêutico , Epilepsia/tratamento farmacológico , Fenfluramina/uso terapêutico , Piperidinas/uso terapêutico , Pregnanolona/análogos & derivados , Piridinas/uso terapêutico , Criança , Humanos , Pregnanolona/uso terapêutico
19.
JAMA Neurol ; 77(3): 300-308, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31790543

RESUMO

Importance: Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens. Objective: To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet syndrome who were taking stiripentol-inclusive regimens. Design, Setting, and Participants: This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens. Interventions: Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients' assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary. Main Outcomes and Measures: The primary efficacy end point was the change in mean monthly convulsive seizure frequency between fenfluramine and placebo during the combined titration and maintenance periods relative to baseline. Results: A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%; P < .001) greater reduction in mean monthly convulsive seizure frequency than those receiving the placebo. With fenfluramine, 54% of patients demonstrated a clinically meaningful (≥50%) reduction in monthly convulsive seizure frequency vs 5% with placebo (P < .001). The median (range) longest seizure-free interval was 22 (3.0-105.0) days with fenfluramine and 13 (1.0-40.0) days with placebo (P = .004). The most common adverse events were decreased appetite (19 patients taking fenfluramine [44%] vs 5 taking placebo [11%]), fatigue (11 [26%] vs 2 [5%]), diarrhea (10 [23%] vs 3 [7%]), and pyrexia (11 [26%] vs 4 [9%]). Cardiac monitoring demonstrated no clinical or echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension. Conclusions and Relevance: Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet syndrome. Trial Registration: ClinicalTrials.gov identifier: NCT02926898.


Assuntos
Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsias Mioclônicas/tratamento farmacológico , Fenfluramina/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Adolescente , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Dioxolanos/uso terapêutico , Método Duplo-Cego , Epilepsia Resistente a Medicamentos/etiologia , Quimioterapia Combinada/métodos , Epilepsias Mioclônicas/complicações , Feminino , Humanos , Masculino
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