Fenfluramine: A Review of Pharmacology, Clinical Efficacy, and Safety in Epilepsy

Samanta, Debopam

doi:10.3390/children9081159

Cited by 17 publications

(10 citation statements)

References 93 publications

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“…Epilepsies, and especially childhood epilepsies, are known to present pharmaco-resistant seizures, highlighting the need of designing targeted therapeutic strategies. With the objective of evaluating different known antiepileptic drugs, three different compounds were selected: valproic acid, which enhances the inhibitory neurotransmission through GABA potentiation and sodium and calcium voltage-gated channels modulation, overall decreasing neuronal excitability and firing rate [ 46 , 47 , 48 ]; topiramate, whose mechanism of action is the increase of GABA activity and inhibition of glutamatergic activity (NMDAR antagonism) through GABA potentiation and sodium and calcium channels modulation [ 49 ]; and fenfluramine, which acts as an agonist of the serotonin 5-HT2 receptors and σ1 receptor positive modulator [ 50 , 51 , 52 ]. We speculated that the treatment of photosensitive crispants with effective antiepileptic drugs would reduce the number of seizure-like events, resulting in a reduced presence of treated crispants in the region of “high activity”.…”

Section: Resultsmentioning

confidence: 99%

A Zebrafish-Based Platform for High-Throughput Epilepsy Modeling and Drug Screening in F0

Locubiche,

Ordóñez,

Abad

et al. 2024

IJMS

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The zebrafish model has emerged as a reference tool for phenotypic drug screening. An increasing number of molecules have been brought from bench to bedside thanks to zebrafish-based assays over the last decade. The high homology between the zebrafish and the human genomes facilitates the generation of zebrafish lines carrying loss-of-function mutations in disease-relevant genes; nonetheless, even using this alternative model, the establishment of isogenic mutant lines requires a long generation time and an elevated number of animals. In this study, we developed a zebrafish-based high-throughput platform for the generation of F0 knock-out (KO) models and the screening of neuroactive compounds. We show that the simultaneous inactivation of a reporter gene (tyrosinase) and a second gene of interest allows the phenotypic selection of F0 somatic mutants (crispants) carrying the highest rates of mutations in both loci. As a proof of principle, we targeted genes associated with neurodevelopmental disorders and we efficiently generated de facto F0 mutants in seven genes involved in childhood epilepsy. We employed a high-throughput multiparametric behavioral analysis to characterize the response of these KO models to an epileptogenic stimulus, making it possible to employ kinematic parameters to identify seizure-like events. The combination of these co-injection, screening and phenotyping methods allowed us to generate crispants recapitulating epilepsy features and to test the efficacy of compounds already during the first days post fertilization. Since the strategy can be applied to a wide range of indications, this study paves the ground for high-throughput drug discovery and promotes the use of zebrafish in personalized medicine and neurotoxicity assessment.

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Section: Resultsmentioning

confidence: 99%

A Zebrafish-Based Platform for High-Throughput Epilepsy Modeling and Drug Screening in F0

Locubiche,

Ordóñez,

Abad

et al. 2024

IJMS

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“…Serotoninergic activity, which raises serotonin (5-hydroxytryptamine) levels in the brain by inducing their release from vesicular storage sites and also by inhibiting their reuptake to increase GABAergic signaling, is thought to be the primary anti-epileptic mechanism of FFA ( 37–39 ). In addition, FFA also reacts with sigma-1 receptors which may bind to N-methyl-D-aspartate (NMDA) and G-protein coupled receptors to control Ca 2+ influx to decrease glutamatergic excitability and then exerts a potential anti-epileptic effect ( 22 , 39 , 40 ). In this study, we investigated the efficacy, safety, and tolerability of different doses of add-on FFA in the treatment of both DS and LGS.…”

Section: Discussionmentioning

confidence: 99%

Optimal dose of fenfluramine in adjuvant treatment of drug-resistant epilepsy: evidence from randomized controlled trials

Xu,

Chen,

Liu

2024

Front. Neurol.

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ObjectiveSeveral clinical trials have suggested that fenfluramine (FFA) is effective for the treatment of epilepsy in Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS). However, the exploration of its optimal target dose is ongoing. This study aimed to summarize the best evidence to inform this clinical issue.Materials and methodsWe searched PubMed, Embase (via Ovid), and Web of Science for relevant literature published before December 1st, 2023. Randomized, double-blind, placebo-controlled studies that evaluated the efficacy, safety, and tolerability of FFA in DS and LGS were identified and meta-analysis was performed according to doses. The study was registered with PROSPERO (CRD42023392454).ResultsSix hundred and twelve patients from four randomized controlled trials were enrolled. The results demonstrated that FFA at 0.2, 0.4, or 0.7 mg/kg/d showed significantly greater efficacy compared to placebo in terms of at least 50% reduction (p < 0.001, p < 0.001, p < 0.001) and at least 75% reduction (p < 0.001, p = 0.007, p < 0.001) in monthly seizure frequency from baseline. Moreover, significantly more patients receiving FFA than placebo were rated as much improved or very much improved in CGI-I by both caregivers/parents and investigators (p < 0.001). The most common treatment-emergent adverse events were decreased appetite, diarrhea, fatigue, and weight loss, with no valvular heart disease or pulmonary hypertension observed in any participant. For dose comparison, 0.7 mg/kg/d group presented higher efficacy on at least 75% reduction in seizure (p = 0.006) but not on at least 50% reduction. Weight loss (p = 0.002), decreased appetite (p = 0.04), and all-cause withdrawal (p = 0.036) were more common in 0.7 mg/kg/d group than 0.2 mg/kg/d. There was no statistical difference in other safety parameters between these two groups.ConclusionThe higher range of the licensed dose achieves the optimal balance between efficacy, safety, and tolerability in patients with DS and LGS.Clinical trial registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023392454.

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“…To identify further studies evaluating the use of FFA in SE, we performed a systematic literature search in the MEDLINE, Cochrane Central Register of Controlled Trials, and Excerpta Medica databases from 1996 until November 2023, using a combined search strategy including the following keywords: “fenfluramine”, “epilepsy”, “seizure”, “Dravet”, “Lennox–Gastaut”, “epileptic encephalopathy”, and “status epilepticus”. We examined the reference lists of all identified studies and review articles on FFA [ 9 , 18 ] for additional relevant studies and reports.…”

Section: Methodsmentioning

confidence: 99%

Fenfluramine for the treatment of status epilepticus: use in an adult with Lennox–Gastaut syndrome and literature review

Strzelczyk,

Becker,

Tako

et al. 2024

Neurol. Res. Pract.

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Background Novel treatments are needed to control refractory status epilepticus (SE). This study aimed to assess the potential effectiveness of fenfluramine (FFA) as an acute treatment option for SE. We present a summary of clinical cases where oral FFA was used in SE. Methods A case of an adult patient with Lennox–Gastaut syndrome (LGS) who was treated with FFA due to refractory SE is presented in detail. To identify studies that evaluated the use of FFA in SE, we performed a systematic literature search. Results Four case reports on the acute treatment with FFA of SE in children and adults with Dravet syndrome (DS) and LGS were available. We report in detail a 30-year-old woman with LGS of structural etiology, who presented with generalized tonic and dialeptic seizures manifesting at high frequencies without a return to clinical baseline constituting the diagnosis of SE. Treatment with anti-seizure medications up to lacosamide 600 mg/d, brivaracetam 300 mg/d, valproate 1,600 mg/d, and various benzodiazepines did not resolve the SE. Due to ongoing refractory SE and following an unremarkable echocardiography, treatment was initiated with FFA, with an initial dose of 10 mg/d (0.22 mg/kg body weight [bw]) and fast up-titration to 26 mg/d (0.58 mg/kg bw) within 10 days. Subsequently, the patient experienced a resolution of SE within 4 days, accompanied by a notable improvement in clinical presentation and regaining her mobility, walking with the assistance of physiotherapists. In the three cases reported in the literature, DS patients with SE were treated with FFA, and a cessation of SE was observed within a few days. No treatment-emergent adverse events were observed during FFA treatment in any of the four cases. Conclusions Based on the reported cases, FFA might be a promising option for the acute treatment of SE in patients with DS and LGS. Observational data show a decreased SE frequency while on FFA, suggesting a potentially preventive role of FFA in these populations. Key points We summarize four cases of refractory status epilepticus (SE) successfully treated with fenfluramine. Refractory SE resolved after 4–7 days on fenfluramine. Swift fenfluramine up-titration was well-tolerated during SE treatment. Treatment-emergent adverse events on fenfluramine were not observed. Fenfluramine might be a valuable acute treatment option for SE in Dravet and Lennox–Gastaut syndromes.

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Fenfluramine: A Review of Pharmacology, Clinical Efficacy, and Safety in Epilepsy

Cited by 17 publications

References 93 publications

A Zebrafish-Based Platform for High-Throughput Epilepsy Modeling and Drug Screening in F0

A Zebrafish-Based Platform for High-Throughput Epilepsy Modeling and Drug Screening in F0

Optimal dose of fenfluramine in adjuvant treatment of drug-resistant epilepsy: evidence from randomized controlled trials

Fenfluramine for the treatment of status epilepticus: use in an adult with Lennox–Gastaut syndrome and literature review

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