大麻二酚在儿童和成人耐药性癫痫的长期安全性和治疗效果评价：基于扩大受试试验的结果_Journal of Epilepsy

Authors：

 SzaflarskiJP , BebinEM , ComiAM , 林岷涛　译 , 高慧　慕洁　审

Corresponding author：

SzaflarskiJP, Email: jszaflarski@uabmc.edu

Keywords：

大麻二酚; 难治性癫痫; 安全性; 有效性

DOI：

10.7507/2096-0247.20190077

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自 2014 年以来，该研究小组进行了一项扩大受试研究（Expanded‐access program，EAP），对难治性癫痫（Treatment‐resistant epilepsies，TRE）患者添加使用了大麻二酚（Cannabidiol，CBD）药物。报告截至 2016 年 12 月关于 CBD 的安全性和有效性的中期结果。研究纳入了 25 个位于美国的医学中心，这些中心招募了服用稳定剂量抗癫痫药物（AEDs）的难治性癫痫患者。在 4 周的基线期内，患者 1 监护人记录所有可计数的癫痫发作类型和次数。患者口服 CBD 的起始剂量为 2～10 mg /（kg·d），最大剂量定为 25～50 mg /（kg·d）。在初始的 16 周内每 2～4 周对患者进行一次访视，此后每 2～12 周进行一次访视。研究数据包括每月惊厥性癫痫和总癫痫发作频率与基线相比的百分比变化，以及与基线相比癫痫发作减少≥50%、≥75% 和 100% 的患者百分比。最后对数据进行描述性分析，使用末次观测值结转法（LOCF 法）来分析丢失的数据。每次访视均记录不良事件（Adverse events，AEs）。安全性分析囊括了 607 例患者，其中有 146 例（24%）退出；最常见的原因是缺乏疗效［89（15%）］和 AEs［32（5%）］。患者的平均年龄为 13 岁（范围为 0.4～62）。联用 AEDs 的数量为 3 种（范围为 0～10）。CBD 的中位剂量为 25 mg /（kg·d）；中位治疗时间为 48 周。联用 CBD 后，在第 12 周时，每月惊厥发作的中位数减少了 51%，总癫痫发作减少了 48%，结果与随访 96 周后的发作次数相似。在第 12 周，惊厥性癫痫发作减少百分比≥50%、≥75% 和 100% 患者比例分别为 52%、31% 和 11%，此结果与 96 周时相似。CBD 的耐受性一般；最常见的 AEs 为腹泻（29%）和嗜睡（22%）。

Citation： SzaflarskiJP, BebinEM, ComiAM, 林岷涛　译, 高慧　慕洁　审. 大麻二酚在儿童和成人耐药性癫痫的长期安全性和治疗效果评价：基于扩大受试试验的结果. Journal of Epilepsy, 2019, 5(6): 475-481. doi: 10.7507/2096-0247.20190077 Copy

1.	Perry MS. Don't fear the reefer-evidence mounts for plant-based cannabidiol as treatment for epilepsy. Epilepsy Curr, 2019, 19(2): 93-95.
2.	Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patientswith treatment‐resistant epilepsy: an open‐label interventionaltrial. Lancet Neurol, 2016, 15: 270-278.
3.	Patel A, Devinsky O, Cross JH, et al. Cannabidiol (CBD) significantly reduces drop seizure frequency in Lennox‐Gastaut syndrome (LGS): results of a dose‐ranging, multi‐center, randomized, double‐blind, placebo‐controlled trial (GWPCARE3). Neurology, 2017, 89(3): e100.
4.	Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet, 2018, 391(10125): 1085-1096.
5.	Jones NA, Glyn SE, Akiyama S, et al. Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure, 2012, 21(5): 344-352.
6.	Jones NA, Hill AJ, Smith I, et al. Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharmacol Exp Ther, 2010, 332(2): 569-577.
7.	Gofshteyn JS, Wilfong A, Devinsky O, et al. Cannabidiol as a potential treatment for febrile infection-related epilepsy syndrome (fires) in the acute and chronic phases. J Child Neurol, 2017, 32(1): 35-40.
8.	Hess EJ, Moody KA, Geffrey AL, et al. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia, 2016, 57(10): 1617-1624.
9.	Toledo M, Beale R, Evans JS, et al. Long-term retention rates for antiepileptic drugs: a review of long-term extension studies and comparison with brivaracetam. Epilepsy Res, 2017, 138: 53-61.
10.	Janssen Korea Ltd. An observational study to evaluate long-termretention rate of topiramate in participants with epilepsy, 2013. Available from https://clinicaltrials.gov/ct2/show/NCT01682681.
11.	Gaston T, Szaflarski M, Hansen B, et al. Improvement in quality of life ratings after one year of treatment with pharmaceutical formulation of cannabidiol (CBD). Epilepsia, 2017, 58(suppl): 155.
12.	Rosenberg EC, Louik J, Conway E, et al. Quality of life in childhood epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol. Epilepsia, 2017, 58(8): e96-e100.
13.	DeWolfe JL, Bebin EM, Cutter GR, et al. Effects of pharmaceutical grade cannabidiol on seizure frequency. American EpilepsySociety Abstracts Database (Abst. 2.100). Available from: https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/195499 Accessed May 7, 2018.
14.	Gaston TE, Bebin EM, Cutter GR, et al. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia, 2017, 58(9): 1586-1592.
15.	Sommerville K, Crockett J, Blakey GE, et al. Bidirectionaldrug-drug interaction with coadministration of cannabidiol andclobazam in a phase 1 healthy volunteer trial. American EpilepsySociety Abstracts Database (Abst. 1. 433). Available from: https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/381188 Accessed May 7, 2018.
16.	Devinsky O, Patel AD, Thiele EA, et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology, 2018, 90(14): e1204-e1211.
17.	Grayson L, Vines B, Nichol K, et al. An interaction between warfarin and cannabidiol, a casereport. Epilepsy Behav Case Rep, 2018, 9(2): 10-11.

1. Perry MS. Don't fear the reefer-evidence mounts for plant-based cannabidiol as treatment for epilepsy. Epilepsy Curr, 2019, 19(2): 93-95.
2. Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patientswith treatment‐resistant epilepsy: an open‐label interventionaltrial. Lancet Neurol, 2016, 15: 270-278.
3. Patel A, Devinsky O, Cross JH, et al. Cannabidiol (CBD) significantly reduces drop seizure frequency in Lennox‐Gastaut syndrome (LGS): results of a dose‐ranging, multi‐center, randomized, double‐blind, placebo‐controlled trial (GWPCARE3). Neurology, 2017, 89(3): e100.
4. Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet, 2018, 391(10125): 1085-1096.
5. Jones NA, Glyn SE, Akiyama S, et al. Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure, 2012, 21(5): 344-352.
6. Jones NA, Hill AJ, Smith I, et al. Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharmacol Exp Ther, 2010, 332(2): 569-577.
7. Gofshteyn JS, Wilfong A, Devinsky O, et al. Cannabidiol as a potential treatment for febrile infection-related epilepsy syndrome (fires) in the acute and chronic phases. J Child Neurol, 2017, 32(1): 35-40.
8. Hess EJ, Moody KA, Geffrey AL, et al. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia, 2016, 57(10): 1617-1624.
9. Toledo M, Beale R, Evans JS, et al. Long-term retention rates for antiepileptic drugs: a review of long-term extension studies and comparison with brivaracetam. Epilepsy Res, 2017, 138: 53-61.
10. Janssen Korea Ltd. An observational study to evaluate long-termretention rate of topiramate in participants with epilepsy, 2013. Available from https://clinicaltrials.gov/ct2/show/NCT01682681.
11. Gaston T, Szaflarski M, Hansen B, et al. Improvement in quality of life ratings after one year of treatment with pharmaceutical formulation of cannabidiol (CBD). Epilepsia, 2017, 58(suppl): 155.
12. Rosenberg EC, Louik J, Conway E, et al. Quality of life in childhood epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol. Epilepsia, 2017, 58(8): e96-e100.
13. DeWolfe JL, Bebin EM, Cutter GR, et al. Effects of pharmaceutical grade cannabidiol on seizure frequency. American EpilepsySociety Abstracts Database (Abst. 2.100). Available from: https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/195499 Accessed May 7, 2018.
14. Gaston TE, Bebin EM, Cutter GR, et al. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia, 2017, 58(9): 1586-1592.
15. Sommerville K, Crockett J, Blakey GE, et al. Bidirectionaldrug-drug interaction with coadministration of cannabidiol andclobazam in a phase 1 healthy volunteer trial. American EpilepsySociety Abstracts Database (Abst. 1. 433). Available from: https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/381188 Accessed May 7, 2018.
16. Devinsky O, Patel AD, Thiele EA, et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology, 2018, 90(14): e1204-e1211.
17. Grayson L, Vines B, Nichol K, et al. An interaction between warfarin and cannabidiol, a casereport. Epilepsy Behav Case Rep, 2018, 9(2): 10-11.

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Journal of Epilepsy

大麻二酚在儿童和成人耐药性癫痫的长期安全性和治疗效果评价：基于扩大受试试验的结果

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