乙琥胺

Ethosuximide
临床资料
商品名（英语：Drug nomenclature）	Zarontin, others
AHFS/Drugs.com	Monograph
MedlinePlus	a682327
核准状况	美 DailyMed: Ethosuximide;
怀孕分级	澳: D ; ;
给药途径	口服(胶囊剂, 溶液(糖浆))
ATC码	N03AD01 (WHO) ;
法律规范状态
法律规范	欧：Rx-only; 美：处方药（℞-only）; 处方药（℞-only）;
药物动力学数据
生物利用度	93%
药物代谢	肝脏 (CYP3A4, CYP2E1（英语：CYP2E1）)
生物半衰期	53小时
排泄途径	肾 (20%)
识别信息
	IUPAC命名法 (RS)-3-Ethyl-3-methyl-pyrrolidine-2,5-dione; ;
CAS号	77-67-8
PubChem CID	3291;
IUPHAR/BPS	7182;
DrugBank	DB00593 ;
ChemSpider	3175 ;
UNII	5SEH9X1D1D;
KEGG	D00539 ;
ChEBI	CHEBI:4887 ;
ChEMBL	ChEMBL696 ;
CompTox Dashboard（英语：CompTox Chemicals Dashboard） (EPA)	DTXSID7023019 ;
ECHA InfoCard	100.000.954
化学信息
化学式	C7H11NO2
摩尔质量	141.17 g·mol−1
3D模型（JSmol（英语：JSmol））	交互式图像;
手性	外消旋体
熔点	64至65 °C（147至149 °F）
	SMILES O=C1NC(=O)CC1(C)CC;
	InChI InChI=1S/C7H11NO2/c1-3-7(2)4-5(9)8-6(7)10/h3-4H2,1-2H3,(H,8,9,10) ; Key:HAPOVYFOVVWLRS-UHFFFAOYSA-N ;

乙琥胺（INN:ethosuximide）以商品名称Zarontin等于市场上销售，是一种用于治疗失神性癫痫发作（英语：absence seizures）的药物。^[4]

此药物可单独使用，或是与其他抗癫痫药物（如丙戊酸）合并使用。^[4]乙琥胺经由口服方式给药。^[4]

人体对于乙琥胺的耐受性通常良好。^[5]使用后常见的副作用有食欲不振、腹痛、腹泻和疲倦感。^[4]严重的副作用有产生自杀意念（英语：Suicide ideation）、血球减少症（英语：Cytopenia）和红斑性狼疮。^[4]^[5]目前尚不清楚个体于怀孕期间服用是否会对胎儿产生不良影响。^[4]乙琥胺属于丁二酰亚胺类药物。其作用机制被认为是透过拮抗神经元突触后的T型钙离子通道（英语：T-type calcium channel）而发挥。^[6]

乙琥胺于1960年在美国获得批准用于医疗用途。^[7]它已列入世界卫生组织基本药物标准清单之中。^[8]市面上有其通用名药物（学名药）贩售。^[4]截至2019年，乙琥胺在许多国家都难以取得，而美国市场则存在药厂有操控售价（英语：price fixing）的质疑。^[9]^[10]^[11]

医疗用途

乙琥胺已获准用于治疗失神性癫痫发作，^[12]且被认为是治疗此类发作的首选药物，部分原因是它不像另一种治疗失神性癫痫的药物 - 丙戊酸 - 般具有特异性的肝毒性。^[13]

不良反应

乙琥胺与其他抗癫痫药物相同，在怀孕期间使用需要谨慎。目前没明确证据，证明此药物会直接导致胎儿发生先天性缺陷。而即使是轻微的癫痫发作对母亲和胎儿都有已知风险，因此医生在开立乙琥胺给孕妇使用时，需要仔细权衡其潜在的风险和益处后才做决定。^[4]

对中枢神经系统

常见

罕见

思觉失调
性欲增强
忧郁加剧

消化道

消化不良
呕吐
恶心
痛性痉挛
便秘
腹泻
腹痛
食欲不振
体重降低
牙龈肿胀（英语：gum enlargement）
舌头肿胀
肝脏功能障碍

泌尿生殖系统

显微性血尿
阴道出血

血液

以下情况可能发生，无论是否有骨髓功能丧失：

皮肤

眼睛

近视

药物交互作用

进行丙戊酸盐与乙琥胺的联合治疗方案时，丙戊酸盐可能会增或减低人体中乙琥胺的血药浓度。然而药理学研究显示丙戊酸盐与乙琥胺联合使用，相较于单一药物治疗，会具更高的保护指数。^[14]

乙琥胺会提高血清中苯妥英的浓度。

作用机转

乙琥胺被认为主要透过阻断神经细胞上的T型钙离子通道来抑制癫痫发作，^[6]但也可能影响其他离子通道。早期研究结果不一致，后续实验证实其能阻断所有亚型。神经元突触富含此通道，早期实验若未纳入考量神经元树突中丰富的T型钙离子通道，则可能无法准确评估乙琥胺的药理作用，进而影响实验结果的可靠性。研究显示乙琥胺能降低丘脑神经元的T型钙离子电流，且具电压依赖性。然而，部分研究未能观察到此效应，甚至发现乙琥胺可能需高浓度或透过降低钠离子电流来作用。近期研究则指出，乙琥胺及其代谢物能有效阻断复制的T型钙离子通道，机制可能涉及物理性阻塞通道。

立体化学

乙琥胺是一种具有立体中心的手性药物（英语：chiral drug）。在治疗上，使用的是外消旋体，即 (S) 和 (R) 异构体的1:1混合物。^[15]

乙琥胺的对映异构
CAS-Nummer: 39122-20-8	CAS-Nummer: 39122-19-5

社会与文化

成本

截至2019年，美国曾有关于乙琥胺价格被制造商哄抬的疑虑。^[11]^[16]

供应情况

乙琥胺在许多国家仅能有限供应。^[9]它曾以商品名Emeside和Zarontin销售。然而这两种品牌的胶囊制剂都已停产，仅剩通用名药物在市场上贩售。Laboratories for Applied Biology于2005年停产Emeside胶囊。^[17]而辉瑞制药于2007年停产Zarontin胶囊。^[18]但此两品牌的糖浆制剂仍在供应中。

参见

参考文献

^ List of nationally authorised medicinal products (PDF). European Medicines Agency.
^ Patsalos PN. Properties of antiepileptic drugs in the treatment of idiopathic generalized epilepsies. Epilepsia. November 2005,. 46 Suppl 9 (s9): 140–8. PMID 16302888. S2CID 19462889. doi:10.1111/j.1528-1167.2005.00326.x .
^ Anvisa. RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control]. Diário Oficial da União（英语：Diário Oficial da União）. 2023-03-31 (2023-04-04) [2023-08-16]. （原始内容存档于2023-08-03）（巴西葡萄牙语）.
^ ^4.0 ^4.1 ^4.2 ^4.3 ^4.4 ^4.5 ^4.6 ^4.7 Ethosuximide. The American Society of Health-System Pharmacists. [2016-12-08]. （原始内容存档于2016-12-21）.
^ ^5.0 ^5.1 World Health Organization. Stuart MC, Kouimtzi M, Hill SR , 编. WHO Model Formulary 2008. World Health Organization. 2009: 69, 74–75. ISBN 9789241547659. hdl:10665/44053 .
^ ^6.0 ^6.1 Huguenard, John R. Block of T -Type Ca2+ Channels Is an Important Action of Succinimide Antiabsence Drugs. Epilepsy Currents. March 2002, 2 (2): 49–52. PMC 320968 . PMID 15309165. doi:10.1046/j.1535-7597.2002.00019.x.
^ Drugs@FDA: FDA-Approved Drugs. U.S. Food and Drug Administration. [2020-12-29]. （原始内容存档于2017-06-29）.
^ World Health Organization. World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. hdl:10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^ ^9.0 ^9.1 Hempel, Georg. Methods of Therapeutic Drug Monitoring Including Pharmacogenetics. Elsevier. 2019: 241. ISBN 978-0-444-64067-3 （英语）.
^ Attorney General Tong leads 44-state coalition in antitrust lawsuit against Teva Pharmaceuticals, 19 other generic drug manufacturers, 15 individuals in conspiracy to fix prices and allocate markets for more than 100 different generic drugs (新闻稿). Office of the Attorney General of the State of Connecticut. 2019-05-12 [2020-04-05]. （原始内容存档于2020-04-20）.
^ ^11.0 ^11.1 States sue generic drug makers, claiming a conspiracy to fix prices. consumeraffairs.com. 2019-05-14 [2020-04-05]. （原始内容存档于2020-04-25）（英语）.
^ Pharmaceutical Associates, Incorporated. Ethosuximide Approval Label (PDF). Label and Approval History. Food and Drug Administration Center for Drug Evaluation and Research. 2000 [2006-02-05]. （原始内容存档 (PDF)于2014-02-28）.
^ Katzung, B. (编). Drugs used in generalized seizures. Basic and Clinical Pharmacology 9th. Lange Medical Books/McGraw-Hill. 2003. ISBN 0071410929.
^ Bourgeois BF. Combination of valproate and ethosuximide: antiepileptic and neurotoxic interaction. The Journal of Pharmacology and Experimental Therapeutics. December 1988, 247 (3): 1128–32. PMID 3144596.
^ Rote Liste Service GmbH (Hrsg.): Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, ISBN 978-3-946057-10-9, S. 182.
^ Staff, WMBF News. South Carolina joins lawsuit against manufacturers in alleged conspiracy to fix prescription drug prices. wmbfnews.com. [2020-04-05]. （原始内容存档于2019-05-13）.
^ Concern over ethosuximide capsule discontinuation. Pharm J. 2005-10-29, 275: 539 [2008-08-31]. （原始内容存档于2008-10-13）. (paywalled archive)
^ Zarontin capsules discontinued. [2012-10-24]. （原始内容存档于2012-06-26）.

[1] List of nationally authorised medicinal products (PDF). European Medicines Agency.

[bioavailability-2] Patsalos PN. Properties of antiepileptic drugs in the treatment of idiopathic generalized epilepsies. Epilepsia. November 2005,. 46 Suppl 9 (s9): 140–8. PMID 16302888. S2CID 19462889. doi:10.1111/j.1528-1167.2005.00326.x .

[3] Anvisa. RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control]. Diário Oficial da União（英语：Diário Oficial da União）. 2023-03-31 (2023-04-04) [2023-08-16]. （原始内容存档于2023-08-03）（巴西葡萄牙语）.

[AHFS2016-4] 4.0 ^4.1 ^4.2 ^4.3 ^4.4 ^4.5 ^4.6 ^4.7 Ethosuximide. The American Society of Health-System Pharmacists. [2016-12-08]. （原始内容存档于2016-12-21）.

[WHO2008-5] 5.0 ^5.1 World Health Organization. Stuart MC, Kouimtzi M, Hill SR , 编. WHO Model Formulary 2008. World Health Organization. 2009: 69, 74–75. ISBN 9789241547659. hdl:10665/44053 .

[Ca2+_Channels-6] 6.0 ^6.1 Huguenard, John R. Block of T -Type Ca2+ Channels Is an Important Action of Succinimide Antiabsence Drugs. Epilepsy Currents. March 2002, 2 (2): 49–52. PMC 320968 . PMID 15309165. doi:10.1046/j.1535-7597.2002.00019.x.

[fdaApproved-7] Drugs@FDA: FDA-Approved Drugs. U.S. Food and Drug Administration. [2020-12-29]. （原始内容存档于2017-06-29）.

[WHO21st-8] World Health Organization. World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. hdl:10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.

[Hem2019-9] 9.0 ^9.1 Hempel, Georg. Methods of Therapeutic Drug Monitoring Including Pharmacogenetics. Elsevier. 2019: 241. ISBN 978-0-444-64067-3 （英语）.

[10] Attorney General Tong leads 44-state coalition in antitrust lawsuit against Teva Pharmaceuticals, 19 other generic drug manufacturers, 15 individuals in conspiracy to fix prices and allocate markets for more than 100 different generic drugs (新闻稿). Office of the Attorney General of the State of Connecticut. 2019-05-12 [2020-04-05]. （原始内容存档于2020-04-20）.

[CA2019-11] 11.0 ^11.1 States sue generic drug makers, claiming a conspiracy to fix prices. consumeraffairs.com. 2019-05-14 [2020-04-05]. （原始内容存档于2020-04-25）（英语）.

[approved_use-12] Pharmaceutical Associates, Incorporated. Ethosuximide Approval Label (PDF). Label and Approval History. Food and Drug Administration Center for Drug Evaluation and Research. 2000 [2006-02-05]. （原始内容存档 (PDF)于2014-02-28）.

[approved_use_2-13] Katzung, B. (编). Drugs used in generalized seizures. Basic and Clinical Pharmacology 9th. Lange Medical Books/McGraw-Hill. 2003. ISBN 0071410929.

[combo-14] Bourgeois BF. Combination of valproate and ethosuximide: antiepileptic and neurotoxic interaction. The Journal of Pharmacology and Experimental Therapeutics. December 1988, 247 (3): 1128–32. PMID 3144596.

[Rote_Liste-15] Rote Liste Service GmbH (Hrsg.): Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, ISBN 978-3-946057-10-9, S. 182.

[16] Staff, WMBF News. South Carolina joins lawsuit against manufacturers in alleged conspiracy to fix prescription drug prices. wmbfnews.com. [2020-04-05]. （原始内容存档于2019-05-13）.

[pharmjethosux-17] Concern over ethosuximide capsule discontinuation. Pharm J. 2005-10-29, 275: 539 [2008-08-31]. （原始内容存档于2008-10-13）. (paywalled archive)

[epiwatchethosux-18] Zarontin capsules discontinued. [2012-10-24]. （原始内容存档于2012-06-26）.

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