芬氟拉明治疗难治性癫痫的研究进展_Journal of Epilepsy

Authors：

李安 ¹ ,  薛国芳 ²

1. ;
2. ;

Corresponding author：

薛国芳, Email: xueguofangty@163.com

Keywords：

芬氟拉明; 难治性癫痫; Dravet综合征; Lennox-Gastaut综合征

DOI：

10.7507/2096-0247.202207003

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

癫痫是神经科常见病，60%在儿童期起病，最终有20%~30%发展为药物难治性癫痫。难治性癫痫是指在使用正确选择且能耐受的两种抗癫痫发作药物的情况下仍不能终止其发作的癫痫，儿童以Lennox-Gastaut综合征（Lennox-Gastaut syndrome，LGS）、Dravet综合征（Dravet syndrome，DS）等为代表，成人以颞叶癫痫为代表。难治性癫痫具有“低治愈率、高致残率、高致死率”的特点，给患者及家属造成巨大的生理和心理上的痛苦。目前，离子类抗癫痫发作药物已难在机制上实现重大突破，而非离子类抗癫痫发作药物的研究则具有广阔的前景，其机制可能涉及癫痫发生的根本机制，而近年来获批上市的芬氟拉明（Fenfluramine，FFA）就属于此类抗癫痫发作药物。多个Ⅲ期随机对照试验研究提示FFA对DS、LGS具有卓越的有效性，为难治性癫痫患者及家属带来了新希望。本文从FFA治疗难治性癫痫的作用机制、药动学、临床疗效、安全性及耐受性等方面进行综述。

Citation： 李安, 薛国芳. 芬氟拉明治疗难治性癫痫的研究进展. Journal of Epilepsy, 2022, 8(6): 544-549. doi: 10.7507/2096-0247.202207003 Copy

1.	吴立文. 难治性癫痫的诊断和治疗. 中华神经科杂志, 2002, 35(1): 55-57.
2.	郭帅, 张冉冉, 刘学伍. 非离子类抗癫痫发作机制及相关药物研究进展. 中华神经科杂志, 2021, 54(6): 612-619.
3.	Nabbout R, Mistry A, Zuberi S, et al. Fenfluramine for treatment-resistant seizures in patients with dravet syndrome receiving stiripentol-inclusive regimens: a randomized clinical trial. JAMA Neurology, 2020, 77(3): 300-308.
4.	Knupp KG, Scheffer IE, Ceulemans B, et al. Efficacy and safety of Fenfluramine for the treatment of seizures associated with Lennox-Gastaut Syndrome: a randomized clinical trial. JAMA Neurol. 2022, 79(6): 554-564.
5.	Lagae L, Sullivan J, Knupp K, et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet, 2019, 394(10216): 2243-2254.
6.	童馨, 慕洁. Dravet综合征——从癫痫性脑病到离子通道病. 癫痫杂志, 2016, 2(3): 264-269.
7.	中国抗癫痫协会创新与转化专委会. Lennox-Gastaut综合征诊断治疗的中国专家共识. 癫痫杂志, 2022, 8(3): 187-195.
8.	Auvin S. Lennox-Gastaut syndrome: new treatments and treatments under investigation. Rev Neurol (Paris), 2020, 176(6): 444-447.
9.	Verrotti A, Striano P, Iapadre G, et al. The pharmacological management of Lennox-Gastaut syndrome and critical literature review. Seizure, 2018, 63: 17-25.
10.	Devinsky O, King L, Schwartz D, et al. Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorder. Epilepsia, 2021, 62(7): e98-e102.
11.	Balagura G, Cacciatore M, Grasso EA, et al. Fenfluramine for the treatment of Dravet Syndrome and Lennox-Gastaut Syndrome. CNS Drugs, 2020, 34(10): 1001-1007.
12.	Strzelczyk A, Schubert-Bast S. A practical guide to the treatment of dravet syndrome with anti-seizure medication. CNS Drugs, 2022, 36(3): 217-237.
13.	Sourbron J, Smolders I, de Witte P, et al. Pharmacological analysis of the anti-epileptic mechanisms of fenfluramine in scn1a mutant zebrafish. Front Pharmacol, 2017, 8: 191.
14.	Polster T. Individualized treatment approaches: Fenfluramine, a novel antiepileptic medication for the treatment of seizures in Dravet syndrome. Epilepsy Behav, 2019, 91: 99-102.
15.	Steriade C, French J, Devinsky O. Epilepsy: key experimental therapeutics in early clinical development. Expert Opin Investig Drugs, 2020, 29(4): 373-383.
16.	Johannessen Landmark C, Potschka H, Auvin S, et al. The role of new medical treatments for the management of developmental and epileptic encephalopathies: Novel concepts and results. Epilepsia, 2021, 62(4): 857-873.
17.	Martin P, Reeder T, Sourbron J, et al. An Emerging role for sigma-1 receptors in the treatment of developmental and epileptic encephalopathies. Int J Mol Sci, 2021, 22(16): 8416.
18.	Rodríguez-Muñoz M, Sánchez-Blázquez P, Garzón J. Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors. Oncotarget, 2018, 9(34): 23373-23389.
19.	谷珊珊, 卢洁. Sigma-1受体在缺血性脑卒中中的研究进展. 卒中与神经疾病, 2021, 28(1): 114-116.
20.	Verrotti A, Striano P. Novel therapeutic options for Dravet and Lennox-Gastaut syndrome. Expert Rev Neurother, 2021, 21(11): 1191-1194.
21.	Odi R, Invernizzi RW, Gallily T, et al. Fenfluramine repurposing from weight loss to epilepsy: what we do and do not know. Pharmacol Ther, 2021, 226: 107866.
22.	Lagae L, Schoonjans AS, Gammaitoni AR, et al. A pilot, open-label study of the effectiveness and tolerability of low-dose ZX008 (fenfluramine HCl) in Lennox-Gastaut syndrome. Epilepsia, 2018, 59(10): 1881-1888.
23.	Sharawat IK, Panda PK, Kasinathan A, et al. Efficacy and tolerability of fenfluramine in patients with Dravet syndrome: a systematic review and meta-analysis. Seizure, 2021, 85: 119-126.
24.	Strzelczyk A, Schubert-Bast S. Expanding the treatment landscape for lennox-gastaut syndrome: current and future strategies. CNS Drugs, 2021, 35(1): 61-83.
25.	Sullivan J, Scheffer IE, Lagae L, et al. Fenfluramine HCl (Fintepla^® ) provides long-term clinically meaningful reduction in seizure frequency: analysis of an ongoing open-label extension study. Epilepsia, 2020, 61(11): 2396-2404.
26.	Geenen KR, Doshi SP, Patel S, et al. Fenfluramine for seizures associated with Sunflower syndrome. Dev Med Child Neurol, 2021, 63(12): 1427-1432.
27.	Lai WW, Galer BS, Wong PC, et al. Cardiovascular safety of fenfluramine in the treatment of Dravet syndrome: analysis of an ongoing long-term open-label safety extension study. Epilepsia, 2020, 61(11): 2386-2395.
28.	Silenieks LB, Carroll NK, Van Niekerk A, et al. Evaluation of selective 5-HT_2C agonists in acute seizure models. ACS Chem Neurosci, 2019, 10(7): 3284-3295.
29.	Simon K, Sheckley H, Anderson CL, et al. A review of fenfluramine for the treatment of Dravet syndrome patients. Curr Res Pharmacol Drug Discov, 2021, 3: 100078.
30.	伍仁琴. 血清素综合征简介. 四川精神卫生, 2001, 16(3): 192-193.
31.	Devinsky O, Hesdorffer DC, Thurman DJ, et al. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol, 2016, 15(10): 1075-1088.
32.	Cross JH, Galer BS, Gil-Nagel A, et al. Impact of fenfluramine on the expected SUDEP mortality rates in patients with Dravet syndrome. Seizure, 2021, 93: 154-159.
33.	Gil-Nagel A, Sullivan J, Ceulemans B, et al. Treatment with fenfluramine in patients with Dravet syndrome has no long-term effects on weight and growth. Epilepsy Behav, 2021, 122: 108212.
34.	Vidaurre J, Herbst J. Nuevos fármacos antiepilépticos [New antiepileptic drugs]. Medicina (B Aires), 2019;79(Suppl 3): 48-53.

1. 吴立文. 难治性癫痫的诊断和治疗. 中华神经科杂志, 2002, 35(1): 55-57.
2. 郭帅, 张冉冉, 刘学伍. 非离子类抗癫痫发作机制及相关药物研究进展. 中华神经科杂志, 2021, 54(6): 612-619.
3. Nabbout R, Mistry A, Zuberi S, et al. Fenfluramine for treatment-resistant seizures in patients with dravet syndrome receiving stiripentol-inclusive regimens: a randomized clinical trial. JAMA Neurology, 2020, 77(3): 300-308.
4. Knupp KG, Scheffer IE, Ceulemans B, et al. Efficacy and safety of Fenfluramine for the treatment of seizures associated with Lennox-Gastaut Syndrome: a randomized clinical trial. JAMA Neurol. 2022, 79(6): 554-564.
5. Lagae L, Sullivan J, Knupp K, et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet, 2019, 394(10216): 2243-2254.
6. 童馨, 慕洁. Dravet综合征——从癫痫性脑病到离子通道病. 癫痫杂志, 2016, 2(3): 264-269.
7. 中国抗癫痫协会创新与转化专委会. Lennox-Gastaut综合征诊断治疗的中国专家共识. 癫痫杂志, 2022, 8(3): 187-195.
8. Auvin S. Lennox-Gastaut syndrome: new treatments and treatments under investigation. Rev Neurol (Paris), 2020, 176(6): 444-447.
9. Verrotti A, Striano P, Iapadre G, et al. The pharmacological management of Lennox-Gastaut syndrome and critical literature review. Seizure, 2018, 63: 17-25.
10. Devinsky O, King L, Schwartz D, et al. Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorder. Epilepsia, 2021, 62(7): e98-e102.
11. Balagura G, Cacciatore M, Grasso EA, et al. Fenfluramine for the treatment of Dravet Syndrome and Lennox-Gastaut Syndrome. CNS Drugs, 2020, 34(10): 1001-1007.
12. Strzelczyk A, Schubert-Bast S. A practical guide to the treatment of dravet syndrome with anti-seizure medication. CNS Drugs, 2022, 36(3): 217-237.
13. Sourbron J, Smolders I, de Witte P, et al. Pharmacological analysis of the anti-epileptic mechanisms of fenfluramine in scn1a mutant zebrafish. Front Pharmacol, 2017, 8: 191.
14. Polster T. Individualized treatment approaches: Fenfluramine, a novel antiepileptic medication for the treatment of seizures in Dravet syndrome. Epilepsy Behav, 2019, 91: 99-102.
15. Steriade C, French J, Devinsky O. Epilepsy: key experimental therapeutics in early clinical development. Expert Opin Investig Drugs, 2020, 29(4): 373-383.
16. Johannessen Landmark C, Potschka H, Auvin S, et al. The role of new medical treatments for the management of developmental and epileptic encephalopathies: Novel concepts and results. Epilepsia, 2021, 62(4): 857-873.
17. Martin P, Reeder T, Sourbron J, et al. An Emerging role for sigma-1 receptors in the treatment of developmental and epileptic encephalopathies. Int J Mol Sci, 2021, 22(16): 8416.
18. Rodríguez-Muñoz M, Sánchez-Blázquez P, Garzón J. Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors. Oncotarget, 2018, 9(34): 23373-23389.
19. 谷珊珊, 卢洁. Sigma-1受体在缺血性脑卒中中的研究进展. 卒中与神经疾病, 2021, 28(1): 114-116.
20. Verrotti A, Striano P. Novel therapeutic options for Dravet and Lennox-Gastaut syndrome. Expert Rev Neurother, 2021, 21(11): 1191-1194.
21. Odi R, Invernizzi RW, Gallily T, et al. Fenfluramine repurposing from weight loss to epilepsy: what we do and do not know. Pharmacol Ther, 2021, 226: 107866.
22. Lagae L, Schoonjans AS, Gammaitoni AR, et al. A pilot, open-label study of the effectiveness and tolerability of low-dose ZX008 (fenfluramine HCl) in Lennox-Gastaut syndrome. Epilepsia, 2018, 59(10): 1881-1888.
23. Sharawat IK, Panda PK, Kasinathan A, et al. Efficacy and tolerability of fenfluramine in patients with Dravet syndrome: a systematic review and meta-analysis. Seizure, 2021, 85: 119-126.
24. Strzelczyk A, Schubert-Bast S. Expanding the treatment landscape for lennox-gastaut syndrome: current and future strategies. CNS Drugs, 2021, 35(1): 61-83.
25. Sullivan J, Scheffer IE, Lagae L, et al. Fenfluramine HCl (Fintepla^® ) provides long-term clinically meaningful reduction in seizure frequency: analysis of an ongoing open-label extension study. Epilepsia, 2020, 61(11): 2396-2404.
26. Geenen KR, Doshi SP, Patel S, et al. Fenfluramine for seizures associated with Sunflower syndrome. Dev Med Child Neurol, 2021, 63(12): 1427-1432.
27. Lai WW, Galer BS, Wong PC, et al. Cardiovascular safety of fenfluramine in the treatment of Dravet syndrome: analysis of an ongoing long-term open-label safety extension study. Epilepsia, 2020, 61(11): 2386-2395.
28. Silenieks LB, Carroll NK, Van Niekerk A, et al. Evaluation of selective 5-HT_2C agonists in acute seizure models. ACS Chem Neurosci, 2019, 10(7): 3284-3295.
29. Simon K, Sheckley H, Anderson CL, et al. A review of fenfluramine for the treatment of Dravet syndrome patients. Curr Res Pharmacol Drug Discov, 2021, 3: 100078.
30. 伍仁琴. 血清素综合征简介. 四川精神卫生, 2001, 16(3): 192-193.
31. Devinsky O, Hesdorffer DC, Thurman DJ, et al. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol, 2016, 15(10): 1075-1088.
32. Cross JH, Galer BS, Gil-Nagel A, et al. Impact of fenfluramine on the expected SUDEP mortality rates in patients with Dravet syndrome. Seizure, 2021, 93: 154-159.
33. Gil-Nagel A, Sullivan J, Ceulemans B, et al. Treatment with fenfluramine in patients with Dravet syndrome has no long-term effects on weight and growth. Epilepsy Behav, 2021, 122: 108212.
34. Vidaurre J, Herbst J. Nuevos fármacos antiepilépticos [New antiepileptic drugs]. Medicina (B Aires), 2019;79(Suppl 3): 48-53.

Previous Article
维生素在癫痫发作中治疗作用的研究进展
Next Article
顶叶内侧—解剖、生理与癫痫

Journal of Epilepsy

芬氟拉明治疗难治性癫痫的研究进展

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content