CN1155241A - Selegilin(思力吉灵)在治疗癫痫病中的应用 - Google Patents
Selegilin(思力吉灵)在治疗癫痫病中的应用 Download PDFInfo
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- CN1155241A CN1155241A CN95194569A CN95194569A CN1155241A CN 1155241 A CN1155241 A CN 1155241A CN 95194569 A CN95194569 A CN 95194569A CN 95194569 A CN95194569 A CN 95194569A CN 1155241 A CN1155241 A CN 1155241A
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- selegilin
- epilepsy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
Abstract
本发明系Selegilin[L-N-(1-苯基异丙基)N-甲基-N-丙烯胺]或其药用盐类在抗癫痫药物中的应用。
Description
本发明涉及Selegilin(＝L-N-(1-苯基异丙基)N-甲基-N-丙烯胺或其药用盐类在抗癫痫药物中的应用。
已经知道Selegilin是B型单胺氧化酶的阻断剂。这种酶在神经胶质细胞中分解单胺能神经递质(特别是多巴胺)，以中止多巴胺的作用。通过阻断酶来提高脑中的多巴胺水平。由于这种作用，Selegilin作为辅助治疗剂与左旋多巴一起用于帕金森氏症的治疗(例如以商标Deprenyl销售者)。
文献中亦曾述及N-(1-苯基异丙基)-N-甲基-N-丙烯胺或确切地说为其L-构型(Selegilin)的其它作用。
在WO 92/17169AI中描述了一种迄今尚不肯定作用机制的神经保护作用。因之它可作为神经保护剂使用(阻止由ZNS病所致神经细胞丧失，特别是帕金森氏症、脑损伤及脊髓的损伤)。
此外，Selegilin的下列作用是已有或尚无合并专利的，但知这些并无明确的作用机制。
于治疗：
a)免疫系统功能障碍，
b)库欣(Cushing)氏综合症，
c)可卡因、酒精和鸦片成瘾的心理戒断症状；
d)衰老症，
e)老年痴呆(Alzheimer)症，
f)戒烟的心理症状，
g)精神分裂症，
h)经前心理症状，
i)晕车、船、飞机(晕动病)，
i)高血压，
k)与其它药剂合并的抑郁症，
(US5 192 808，US4 861 800，US4 868 218， US4 579 870，CA1 322 530，WO92/21333A1，WO91/18592A1，WO90/04387，WO90/01928，WO88/04552，EP252 290A1)
作为进一步的应用，是以标记的Selegilin作神经胶质细胞的标记物对退行性疾病神经胶原的标记，这已被申请专利(US 7052921，US6853119)。在这些适应症中，还描述了由癫痫病人大脑瘢结的外科切除前的神经胶原中心的诊断。这也仅是一种诊断应用。作者肯定在癫痫情况下，单胺氧化酶B没有任何病原性参与，Selegilin只适于标识神经胶质细胞(Kumlien E等，Epilepsia，Vol.33，NO.4，1992)。
为了治疗癫痫，市场上有一些抗惊厥药物。苯妥英(Phenytoin)和酰胺咪嗪(carbamazepin)就是其重要的代表。迄今抗惊厥的治疗只在于抑制痉挛，但这对实际上癫痫病人群的增长并无作用。
目前的这个发明，其任务就是提供具有良好的抗惊厥和抗癫痫作用的药物。
已经惊奇地发现，Selegilin表现出很强的抗惊厥和抗癫痫作用。与标准的抗惊厥药物酰胺咪嗪和苯妥英相比，引起类似强度的集中和普遍痉挛的阈值被提高了。
痉挛阈值是用作抗惊厥作用的重要指标。癫痫也是一种阈值现象，痉挛被引起则是由于人们受内部或外部刺激而超过了阈值。首选作为治疗癫痫的药物是提高此阈值，其次的选择药物才是不常影响阈值只为减少个别发作的痉挛。
在经典的癫痫模型中，最大强度电休克能证实Selegilin对阈值的作用。
药理研究证明Selegilin有和第一选择药物的类似作用。
就癫痫病人而言，其病程中常有疾病发展，而癫痫发作越厉害，专利化合物治疗效果越差。
其特别的意义还在于，Selegilin处在一种减缓癫痫病人群增长并因之制止疾病发展的地位。
N-(1-苯基异丙基)-N-甲基-N-丙烯胺的抗癫痫作用是严格的立体特异性的，只有L-构型(Selegilin)才起抗癫痫作用。
D-构型体是无效的，它在制剂中能引起强烈的安非他明型副作用，L-型体则无副作用。
药理研究
Selegilin研究的出发点是以扁桃体刺激作为暴发性癫痫和致癫痫的模型来判断其神经保护作用。
在扁桃体刺激中，通过深埋电极对大鼠的一个脑区重复非常微弱的刺激诱发一个癫痫病灶。这个病灶是持久的，被完全刺激的动物被作为癫痫看待。在此模型中只能研究抗惊厥作用。动物被完全刺激并引起痉挛，则引起痉挛的阈值就被升高(要引起痉挛，必须给强刺激)，尽管引起的痉挛可能很弱。
此模型还可作药效研究，它的非依赖性的抗痉挛发生作用，抑制癫痫病灶的发展。抗惊厥作用是不依赖于抗癫痫病灶发展的作用的。
抗惊厥作用的资料
依据Freemann FG等的方法，见Brain Res.Bull.，1981，7，629-633；改进的方法见Rundfeldf等，Neuropharmacology，1990，29，845-851。
扁桃体刺激，引起完全刺激大鼠突发痉挛的阈值提高。
| 痉挛阈值的提高，％ | |
| L-型体(Selegilin) | |
| 5mg/kgi.p. | 0 |
| 10mg/kgi.p. | +130-+250 |
| 20mg/kgi.p. | +70 |
| 40mg/kgi.p. | +41 |
| D-型体 | |
| 10mg/kg | -12 |
癫痫病灶在刺激中发展的影响
按照Racine R等人的方法，见Electroencephalograph Clin.Neurophysiol.，1975，38.355-365；亦参见Silver JM等，Ann.Neurol.，1991，29，356-363。
刺激产生的癫痫病灶在大脑中产生成形的变化。就其整体形成癫痫病灶是一个预期的全部过程中不可避免的癫痫发作。
在以Selegilin治疗时(5和10mg/kg，1x/日)，需要多达35％和53％的刺激，才能引起第一次普遍痉挛。此外对一个建立起的病灶，还能显著地延长癫痫发作的必然性(52％和117％)。据此表明，Selegilin对建立的病灶有延续大脑不可避免的成形的病变。
在治疗中断之后，对能够引起整体刺激的动物癫痫发作的期限比起对照动物的来是显著缩短了。
这表明癫痫病灶所表现出的比对照组的略强一些。
因此Selegilin能作为高特异性药物以治疗癫痫病。
它不仅能抑制痉挛，还能延缓病情发展。
本发明的化合物及其制法均系已知。
此化合物能以一般熟知的方式给药，如片剂、胶囊、糖衣片、丸剂、粒剂、糖浆、乳剂、悬浮剂和溶液，同时使用一种惰性无毒的，药理上惰性的载体或者溶质。
Selegilin以口服或分次给药的日剂量共为5-20mg。
若有必要的话上述的用量也可偏离，这当依据体重和特定的给药方式。
Claims (3)
1.Selegilin或药用盐类在治疗癫痫病中的应用。
2.Selegilin或其药用盐类按权利要求1中尤其是在对抑制痉挛和延缓病情发展中的应用。
3.具有抗癫痫作用的含有权利要求1的化合物的药物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4428444.6 | 1994-08-11 | ||
| DE4428444A DE4428444A1 (de) | 1994-08-11 | 1994-08-11 | Verwendung von Selegilin zur Behandlung von epileptischen Erkrankungen |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1155241A true CN1155241A (zh) | 1997-07-23 |
| CN1081918C CN1081918C (zh) | 2002-04-03 |
Family
ID=6525440
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95194569A Expired - Fee Related CN1081918C (zh) | 1994-08-11 | 1995-07-27 | Selegilin(思力吉灵)在治疗癫痫病中的应用 |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US5952388A (zh) |
| EP (1) | EP0774961B1 (zh) |
| JP (1) | JP3922307B2 (zh) |
| CN (1) | CN1081918C (zh) |
| AT (1) | ATE239458T1 (zh) |
| AU (1) | AU691316B2 (zh) |
| BR (1) | BR9508531A (zh) |
| CA (1) | CA2197176C (zh) |
| CZ (1) | CZ285681B6 (zh) |
| DE (2) | DE4428444A1 (zh) |
| DK (1) | DK0774961T3 (zh) |
| EE (1) | EE04176B1 (zh) |
| ES (1) | ES2199252T3 (zh) |
| HU (1) | HU223529B1 (zh) |
| MY (1) | MY116362A (zh) |
| NO (1) | NO314684B1 (zh) |
| PL (1) | PL188040B1 (zh) |
| PT (1) | PT774961E (zh) |
| RU (1) | RU2155584C2 (zh) |
| SK (1) | SK283205B6 (zh) |
| TR (1) | TR199500984A2 (zh) |
| TW (1) | TW448044B (zh) |
| WO (1) | WO1996004897A1 (zh) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19630035A1 (de) * | 1996-07-25 | 1998-01-29 | Asta Medica Ag | Tramadol Multiple Unit Formulierungen |
| DE19716905C1 (de) * | 1997-04-22 | 1998-08-27 | Iip Inst Fuer Ind Pharmazie Fo | Stabile, wäßrige Lösung auf der Grundlage von Selegilin und Vorrichtung zu ihrer Verabreichung |
| DE19743323C2 (de) * | 1997-09-30 | 2000-05-25 | Iip Inst Fuer Ind Pharmazie Fo | Feste Arzneimittelzusammensetzung auf der Grundlage von Selegilin |
| WO2003039525A1 (en) * | 2001-11-05 | 2003-05-15 | Krele Pharmaceuticals Llc | Compositions and methods for increasing compliance with therapies using aldehyde dehydrogenase inhibitors and treating alcoholism |
| GB201715919D0 (en) * | 2017-09-29 | 2017-11-15 | Gw Res Ltd | use of cannabinoids in the treatment of epilepsy |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5192808A (en) * | 1990-08-31 | 1993-03-09 | Deprenyl Animal Health, Inc. | Therapeutic effect of L-deprenyl in the management of pituitary-dependent hyperadrenocorticism (cushing's disease) |
| CA2107552C (en) * | 1991-04-04 | 2001-08-28 | William G. Tatton | Use of deprenyl to maintain, prevent loss, or recover nerve cell function |
| US5648087A (en) * | 1993-03-09 | 1997-07-15 | Sanofi Sante Nutrition Animale | Anaesthetic pharmaceutical composition comprising a general anaesthetic and selegiline |
| US5462740A (en) * | 1993-09-17 | 1995-10-31 | Athena Neurosciences, Inc. | Rectally-administered, epileptic-seizure-inhibiting composition |
-
1994
- 1994-08-11 DE DE4428444A patent/DE4428444A1/de not_active Withdrawn
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1995
- 1995-07-17 TW TW084107378A patent/TW448044B/zh not_active IP Right Cessation
- 1995-07-27 JP JP50690596A patent/JP3922307B2/ja not_active Expired - Fee Related
- 1995-07-27 HU HU9700405A patent/HU223529B1/hu not_active IP Right Cessation
- 1995-07-27 CN CN95194569A patent/CN1081918C/zh not_active Expired - Fee Related
- 1995-07-27 RU RU97104062/14A patent/RU2155584C2/ru not_active IP Right Cessation
- 1995-07-27 US US08/776,931 patent/US5952388A/en not_active Expired - Fee Related
- 1995-07-27 DK DK95925732T patent/DK0774961T3/da active
- 1995-07-27 WO PCT/DE1995/000981 patent/WO1996004897A1/de active IP Right Grant
- 1995-07-27 PT PT95925732T patent/PT774961E/pt unknown
- 1995-07-27 BR BR9508531A patent/BR9508531A/pt not_active Application Discontinuation
- 1995-07-27 PL PL31829295A patent/PL188040B1/pl not_active IP Right Cessation
- 1995-07-27 AU AU29760/95A patent/AU691316B2/en not_active Ceased
- 1995-07-27 ES ES95925732T patent/ES2199252T3/es not_active Expired - Lifetime
- 1995-07-27 EP EP95925732A patent/EP0774961B1/de not_active Expired - Lifetime
- 1995-07-27 DE DE59510674T patent/DE59510674D1/de not_active Expired - Fee Related
- 1995-07-27 CZ CZ97407A patent/CZ285681B6/cs not_active IP Right Cessation
- 1995-07-27 AT AT95925732T patent/ATE239458T1/de not_active IP Right Cessation
- 1995-07-27 CA CA002197176A patent/CA2197176C/en not_active Expired - Fee Related
- 1995-07-27 EE EE9700068A patent/EE04176B1/xx not_active IP Right Cessation
- 1995-07-27 SK SK199-97A patent/SK283205B6/sk not_active IP Right Cessation
- 1995-07-31 MY MYPI95002228A patent/MY116362A/en unknown
- 1995-08-09 TR TR95/00984A patent/TR199500984A2/xx unknown
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1997
- 1997-02-10 NO NO19970607A patent/NO314684B1/no not_active IP Right Cessation
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