芬氟拉明治療難治性癲癇的研究進展_Journal of Epilepsy

Authors：

李安 ¹ ,  薛國芳 ²

1. ;
2. ;

Corresponding?author：

薛國芳, Email: xueguofangty@163.com

Keywords：

芬氟拉明; 難治性癲癇; Dravet綜合征; Lennox-Gastaut綜合征

DOI：

10.7507/2096-0247.202207003

Video：

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癲癇是神經科常見病，60%在兒童期起病，最終有20%~30%發展為藥物難治性癲癇。難治性癲癇是指在使用正確選擇且能耐受的兩種抗癲癇發作藥物的情況下仍不能終止其發作的癲癇，兒童以Lennox-Gastaut綜合征（Lennox-Gastaut syndrome，LGS）、Dravet綜合征（Dravet syndrome，DS）等為代表，成人以顳葉癲癇為代表。難治性癲癇具有“低治愈率、高致殘率、高致死率”的特點，給患者及家屬造成巨大的生理和心理上的痛苦。目前，離子類抗癲癇發作藥物已難在機制上實現重大突破，而非離子類抗癲癇發作藥物的研究則具有廣闊的前景，其機制可能涉及癲癇發生的根本機制，而近年來獲批上市的芬氟拉明（Fenfluramine，FFA）就屬于此類抗癲癇發作藥物。多個Ⅲ期隨機對照試驗研究提示FFA對DS、LGS具有卓越的有效性，為難治性癲癇患者及家屬帶來了新希望。本文從FFA治療難治性癲癇的作用機制、藥動學、臨床療效、安全性及耐受性等方面進行綜述。

Citation： 李安, 薛國芳. 芬氟拉明治療難治性癲癇的研究進展. Journal of Epilepsy, 2022, 8(6): 544-549. doi: 10.7507/2096-0247.202207003 Copy

1.	吳立文. 難治性癲癇的診斷和治療. 中華神經科雜志, 2002, 35(1): 55-57.
2.	郭帥, 張冉冉, 劉學伍. 非離子類抗癲癇發作機制及相關藥物研究進展. 中華神經科雜志, 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, 慕潔. Dravet綜合征——從癲癇性腦病到離子通道病. 癲癇雜志, 2016, 2(3): 264-269.
7.	中國抗癲癇協會創新與轉化專委會. Lennox-Gastaut綜合征診斷治療的中國專家共識. 癲癇雜志, 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-Mu?oz 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, 盧潔. Sigma-1受體在缺血性腦卒中中的研究進展. 卒中與神經疾病, 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. 血清素綜合征簡介. 四川精神衛生, 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. 吳立文. 難治性癲癇的診斷和治療. 中華神經科雜志, 2002, 35(1): 55-57.
2. 郭帥, 張冉冉, 劉學伍. 非離子類抗癲癇發作機制及相關藥物研究進展. 中華神經科雜志, 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, 慕潔. Dravet綜合征——從癲癇性腦病到離子通道病. 癲癇雜志, 2016, 2(3): 264-269.
7. 中國抗癲癇協會創新與轉化專委會. Lennox-Gastaut綜合征診斷治療的中國專家共識. 癲癇雜志, 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-Mu?oz 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, 盧潔. Sigma-1受體在缺血性腦卒中中的研究進展. 卒中與神經疾病, 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. 血清素綜合征簡介. 四川精神衛生, 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.

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