CN1198610C - 神经紊乱的治疗 - Google Patents

神经紊乱的治疗 Download PDF

Info

Publication number
CN1198610C
CN1198610C CNB008100292A CN00810029A CN1198610C CN 1198610 C CN1198610 C CN 1198610C CN B008100292 A CNB008100292 A CN B008100292A CN 00810029 A CN00810029 A CN 00810029A CN 1198610 C CN1198610 C CN 1198610C
Authority
CN
China
Prior art keywords
treatment
test
citalopram
medicine
purposes
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
CNB008100292A
Other languages
English (en)
Other versions
CN1360501A (zh
Inventor
C·桑切兹
S·霍格
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lingbei United Co ltd
H Lundbeck AS
Original Assignee
Lingbei United Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=8099796&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN1198610(C) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Lingbei United Co ltd filed Critical Lingbei United Co ltd
Publication of CN1360501A publication Critical patent/CN1360501A/zh
Application granted granted Critical
Publication of CN1198610C publication Critical patent/CN1198610C/zh
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Psychiatry (AREA)
  • Anesthesiology (AREA)
  • Pain & Pain Management (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Compounds Of Unknown Constitution (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

S-西酞普兰(西酞普兰的S-(+)对映体)或其药用盐用于制备治疗神经紊乱病的用途，包括焦虑状态，特别是一般性精神焦虑和社交性精神焦虑，创伤后紧张失调，强迫观念与行为失调和惊慌发作。

Description

神经紊乱的治疗
                    本发明的领域
本发明涉及化合物S-西酞普兰(escitalopram，INN名)的应用，它是熟知的抗抑郁药西酞普兰(citalopram)的S-对映体，即(S)-1-[3-(二甲基氨基)丙基]-1-(4-氟苯基)-1，3-二氢-5-异苯并呋喃甲腈，或其医药上可用的盐，用于制备治疗神经紊乱，包括精神不宁和惊慌发作的药物。
                    本发明的背景
西酞普兰是熟知的抗抑郁药，已在市场上销售多年，具有以下结构：
式I
它是一种选择性中心作用的5-羟色胺(5-hydroxytryptamine，5-HT)再吸收抑制剂，因而具有抗抑郁活性。该化合物的抗抑郁活性已在一些出版物中有过报道，如J.Hyttel，Prog.Neuro-Psychopharmacol.&Biol.Psychiat.，1982，6，277-295和A.Gravem，Acta Psychiatr.Scand，1987，75，478-486，现在它被销售用以治疗抑郁和惊慌病症。进一步的公开显示该化合物在治理痴呆和脑血管病方面有效，EP-A 474580。
在U.S.P 4943590中公开了S-西酞普兰以及它的制备方法。西酞普兰的立体选择性，即S-对映体的5-HT再吸收抑制，以及该对映体的抗抑郁作用也已公开。目前S-西酞普兰正开发为抗抑郁药。
研究已经表明，神经紊乱病人，包括精神不宁，尤其是一般性的焦虑和惊慌发作，特别是与矿野恐怖相关的病人的生活质量的损害与酒精中毒，精神分裂症或个性失调病人身上可见的伤残相当或更大。而且，目前的治疗不总是有效或引起不可接受的副作用。
因而，在神经紊乱治疗中需要有用的替代治疗。
现已发现，S-西酞普兰在治理惊慌发作和禁不住的分神失调方面，在神经紊乱，例如焦虑作用和突起作用的模式中显示有力的作用。
                    本发明的说明
根据本发明，提供了S-西酞普兰的一种新用途，即用于制备治疗神经紊乱用的药物。
在整个说明书和权利要求中，术语神经紊乱一词指的是一组心理紊乱，包括精神不宁，特别是一般性焦虑和社交性不宁，创伤后紧张失调，强迫观念与行为失调和惊慌发作。
术语一般性焦虑、社交性不宁、心灵创伤后失调和强迫观念与行为失调各词如在DSMIV中所定义。
短语“惊慌发作”考虑任何疾病的治疗，这些疾病是与惊慌发作有关的，包括恐慌失调，特种恐惧，社交恐惧和出现惊慌发作时的旷野恐怖。这些失调进一步如在DSMIV中定义。恐慌发作是一个不连续的时期，此间有强烈的恐惧，畏惧或惊骇突然出现，常与即将发生灾难的感觉有关。在发作期间，出现的症状有抖动，出汗，焦虑，呼吸急促的感觉，气哽的感觉，胸痛或烦闷，恶心，感到头晕，不真实的感觉，失控的害怕或变疯狂，怕染色，感觉异常和寒战或渐红。
惊慌失控的特征是周期性出现不可预计的惊慌发作，对此是持续关注的。旷野恐怖是在发生惊慌时，对于难以逃避在其中不能得到帮助的地方或情况的焦虑，或躲避。特有的恐惧和社交恐惧(原来一起简称恐惧)的特征是明显和持续的害怕，这是过分的或不合理的，是被特定物体或情况(飞行，登高，动物，见血等)或社会展现的情况的出现或提前出现所暗示的。
出现惊慌发作的失控在发作出现的预见性上彼此不同，例如，在惊慌失控中，发作是不可预见的，并与任何具体事件无关，而在特种恐惧中，发作是由特种刺激引起的。
词组“惊慌失调的治疗”意思是减少发作次数或预防发作和/或减轻发作的严重性。类似地，一般性精神焦虑，社交性精神不宁，心灵创伤后的紧张以及强迫观念与行为失调的治疗包括这些疾病的治疗或预防，或减轻其症状。
根据本发明，S-西酞普兰可以用该化合物的碱或其医药上可接受的酸加成盐，或酸酐，或这种盐的水合物。在本发明中应用的该化合物的盐是与无毒的有机或无机酸，特别是草酸形成的盐。
已经发现，S-西酞普兰在“成年大鼠中抑制足颤引起的超声发声”试验中，“小鼠黑与白试验”以及烦渴试验中，显示有不同于外消旋化合物的显著的作用。这些模式是分别对于抗焦虑作用与抗惊慌发作的作用以及强迫观念与行为失调的标准动物模式。
根据本发明，S-西酞普兰或其药学上可接受的盐可以任一适合的途径，如口服或非肠胃的途径给药，为了这种给药，它可以任一适合的形式存在，例如片剂，胶囊，粉末，糖浆或注射用的溶液或分散剂。根据本发明的目的，本发明的化合物优选以固体药，适合片剂或胶囊，或以注射用的悬浮液，溶液或分散液形式来给药。
固体药制剂的制备方法是本领域熟知的。片剂可通过混合活性成分与普通助剂和/或稀释剂，然后在一个方便的制片机中压制混合物来制备，助剂或释释剂的实例包括：玉米淀粉，乳糖，滑石粉，硬脂酸镁，明胶，树胶等，任何其它助剂或添加剂，例如色素，香料，防腐剂等也可采用，条件是它们可与活性成分配伍。
本发明的化合物以单位剂量形式口服给药最方便，例如片剂或胶囊，在一个剂量中含有活性成分从大约1.0mg至50mg，优选5mg/天至40mg/天，最优选10mg/天至20mg/天。
按USP 4943590的介绍可制得S-西酞普兰的草酸盐，其碱或其它药学上可接受的盐可通过标准方法获得。
根据本发明所采用的酸加成盐可通过在惰性溶剂中处理S-西酞普兰与酸来制得，接着通过已知的方法沉淀，分离和选择性重结晶，如果需要，通过湿磨或干磨将结晶产品粉碎成几微米的粒子，或从溶剂-乳化工艺制备颗粒。
药理试验
按对于神经紊乱作用公认、可靠的试验模式试验S-西酞普兰。以西酞普兰-外消旋化合物作对照。
对成年大鼠的足颤引起的发声试验
对年大鼠的足颤引起的发声试验(详细介绍见Sánchez C.，血清药物serotonergic drugs对成年雄性大鼠足颤引起的超声发声的作用。Behav.Pharmacol.1993；4：267-277)是关于抗焦虑作用和抗惊慌作用的试验。
试验程序
在研究之初，采用重150-175g的雄性大鼠(Wistar WU，查尔斯得，德国)。
概括地，采用灰色有机玻璃并装上金属格网地板制造的试验笼(22cm×22cm×22cm)。从两极震动器发出足颤，在试验笼顶盖中央放一个对20-30KHz超声波敏感的麦克风。超声波从麦克风送到前置放大器，在信号整流器中，AC信号转变成DC信号，记下整流器信号的伏特大于原先测定的阈限水平的伏特所累积的时间。
第一试验期间前24小时动物是端端正正的。在每只试验笼中接着放入一只大鼠，此后立即给以每隔10秒一次4个1.0mA的不可逃避足颤，颤动间隔5秒。最初颤动后6分钟，动物从每只试验笼中离开。在试验日内，试验前30分钟给药或盐水。大鼠每隔10秒接收到4个1.0MA的不可逃避足颤，颤动间隔5秒，最后一次颤动后1分钟开始记录超声发声，持续5分钟，记下发声耗费的总时间。一周的消除期之后大鼠可在新的试验期内使用，大鼠总共可用7-8周，在每个试验期，随机分配用盐水或试验药处理动物组。每个试验组有8只动物，在每期内包括1个盐水处理组，2-4个药物处理组。每种药至少用重迭剂量进行2次独立的试验。
结果
试验表明，西酞普兰外消旋化合物的最大作用是60-70％抑制，而S-西酞普兰能完全抑制发声。
黑与白箱试验
这是抗焦虑作用的试验，试验的详细介绍见Sánchez，C.(1995)Pharmacol.Toxico，77，71-78。
试验程序
体重30-35g的雄性小鼠(Lundbeck品系，查尔斯得，德国)分4组居于麦克伦II型笼中，12小时白天/黑夜轮换循环(下竿7点关灯)。试验前小鼠至少在白天/黑夜循环中呆3周。自动控制室温(21±2℃)，相对湿度(55±5％)和换气(每小时16次)。动物可自由取用市售食品丸和水。
如Sánchez(1995)(见上)所介绍，设计试验箱。试验箱(45cm×27cm×27cm)是上开口的，用隔板分成两个隔间(比例2∶3)，隔板面对黑的隔间的一面是黑色的，面对白色隔间的一面是白色的。较小的屋用黑色有机玻璃制成，较大的屋除最低的7.5cm外用白色有机玻璃制成，这部分用透明的有机玻璃(外墙)和黑色有机玻璃(隔板)构成。白隔间通过在隔板中7.5cm×7.5cm的开口与黑隔间连接。白隔间的地板分成9块，黑隔间的地板分成6块。白隔间用发出冷光的Schott KL 1500的电灯照射，相应的光密度为560Lux。小鼠试验系统是全自动化的，在横向2排有11个红外光源和光电池，在纵向1排有16个(较低的一排)。较低一排光电池(在笼地板上方2cm)检测水平的运动活力(横跨，进入，以及每个隔间的时间)，而较高一排光电池(在笼地板上方5cm)检测竖起的活力，同时从4个试验箱记录1分钟间隔的累积数据，并贮存于Paradox数据库中。
试验箱放在黑暗、安静的室内。在暗容器内的小鼠在试验前2小时运到试验室中。试验室用黑帘分成两部分。药物处理发生在使用最小的红光的一部分室内。给药后，直到试验前将小鼠各自放在II型麦克伦笼内。预处理时间是30分钟。试验箱放在室内的另一部分。通过将小鼠放在明亮的白隔间的中央，面对黑隔间的开口，试验时间5分钟，并估测在黑隔间和白隔间内各方块之间竖向和横向跨越的次数，进入黑隔间的次数和在白隔间中消耗的时间。
结果
S-西酞普兰在此模式中显示突出的作用。
人为引起的烦渴
被剥夺食品的大鼠暴露于间断地供给食品的程序之后，如果给它机会将会大量饮水。这种行为现象称之为人为引起的烦渴，可以认为是一种正常行为的过分表达。人为引起的烦渴被认为是一种强迫观念与行为失调的模式(Woods等人，1993)。
试验程序
雄性韦斯塔大鼠(Mllegard)成对居住，在试验开始前2周和整个试验期间保持限食(正常体重的80％)为了引起烦渴，将大鼠放在试验室内，药丸分散器每60秒自动散下1颗60mg的食品丸。在试验室内任何时间均可得到水，每周试验大鼠4-5次，3-4周后，训练70％的大鼠每30分钟试验期间饮水＞10ml。
一旦大鼠已经达到稳定的饮水水平，化合物就可被试验。试验前60分钟和在无试验日的10:00，口服施用西酞普兰(40mg/kg)或Lu26-054(20mg/kg)。水摄入呈现一个施药前的百分数(基线)水平。
结果S-西酞普兰使水摄入明显减少，而西酞普兰无作用
所有这些研究表明，S-西酞普兰有强有力的抗神经病害作用，特别是抗焦虑作用和抗惊慌发作与强迫观念与行为失调的作用。

Claims (7)

1.S-西酞普兰或其药学上可接受的盐在制备用于治疗一般性精神焦虑、创伤后紧张、强迫观念与行为失调、或惊慌发作药物方面的用途。
2.根据权利要求1的用途，其特征在于此药物以单位剂量施药。
3.根据权利要求2的用途，其特征在于单位剂量含有的活性成分量从1.0mg至50mg。
4.权利要求1的用途，其特征在于此药物用于惊慌失调的治疗。
5.权利要求1的用途，其特征在于此药物用于特种恐惧的治疗。
6.权利要求1的用途，其特征在于此药物用于社交性恐惧的治疗。
7.权利要求1的用途，其特征在于此药物用于旷野恐惧的治疗。
CNB008100292A 1999-07-08 2000-07-07 神经紊乱的治疗 Expired - Lifetime CN1198610C (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DKPA199900991 1999-07-08
DKPA199900991 1999-07-08

Publications (2)

Publication Number Publication Date
CN1360501A CN1360501A (zh) 2002-07-24
CN1198610C true CN1198610C (zh) 2005-04-27

Family

ID=8099796

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB008100292A Expired - Lifetime CN1198610C (zh) 1999-07-08 2000-07-07 神经紊乱的治疗

Country Status (38)

Country Link
US (6) US7271194B2 (zh)
EP (4) EP1440691A3 (zh)
JP (1) JP4773011B2 (zh)
KR (1) KR100604176B1 (zh)
CN (1) CN1198610C (zh)
AR (1) AR021155A1 (zh)
AT (1) ATE339955T1 (zh)
AU (6) AU782514B2 (zh)
BG (4) BG106279A (zh)
BR (1) BR0011578A (zh)
CA (4) CA2687394A1 (zh)
CL (3) CL2008003941A1 (zh)
CO (1) CO5190674A1 (zh)
CY (1) CY1105806T1 (zh)
CZ (1) CZ200270A3 (zh)
DE (1) DE60030861T2 (zh)
DK (1) DK1200081T3 (zh)
EA (1) EA006555B1 (zh)
ES (1) ES2272298T3 (zh)
HK (1) HK1048069B (zh)
HR (1) HRP20010820A2 (zh)
HU (1) HUP0201791A3 (zh)
IL (5) IL146131A0 (zh)
IS (1) IS6137A (zh)
ME (2) MEP2508A (zh)
MX (1) MXPA01011626A (zh)
MY (1) MY143278A (zh)
NO (4) NO329021B1 (zh)
PL (1) PL352030A1 (zh)
PT (1) PT1200081E (zh)
SI (1) SI1200081T1 (zh)
SK (1) SK82002A3 (zh)
TR (4) TR200402276T2 (zh)
TW (1) TWI232101B (zh)
UA (1) UA77645C2 (zh)
WO (1) WO2001003694A1 (zh)
YU (1) YU78701A (zh)
ZA (1) ZA200108856B (zh)

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR021155A1 (es) * 1999-07-08 2002-06-12 Lundbeck & Co As H Tratamiento de desordenes neuroticos
GB0005477D0 (en) 2000-03-07 2000-04-26 Resolution Chemicals Limited Process for the preparation of citalopram
EP1301502B1 (en) 2000-07-21 2005-05-18 H. Lundbeck A/S Compounds and their use as glycine transport inhibitors
CN1509169A (zh) * 2001-05-01 2004-06-30 H��¡�±������޹�˾ 对映体纯艾司西酞普兰的用途
JP2005525993A (ja) 2001-07-31 2005-09-02 ハー・ルンドベック・アクチエゼルスカベット エスシタロプラムを含む結晶性組成物
US20040067963A1 (en) * 2002-07-08 2004-04-08 University Of Florida Methods to prevent or ameliorate trauma-related psychological disorders
ATE388947T1 (de) * 2002-12-23 2008-03-15 Lundbeck & Co As H Escitalopramhydrobromid und ein verfahren zu dessen herstellung
US20050137255A1 (en) * 2002-12-23 2005-06-23 H. Lundbeck A/S Crystalline escitalopram hydrobromide and methods for preparing the same
TR200504022T1 (tr) * 2003-03-24 2006-08-21 Hetero Drugs Limited (S)-sitalopram oksalatın yeni sıvı kristal formları.
US20090093461A1 (en) * 2003-07-02 2009-04-09 Astrazeneca Ab Methods of Treating Anxiety and Mood Disorders
US7855195B2 (en) * 2003-12-02 2010-12-21 Pharmaneuroboost N.V. Method of treating mental disorders using D4 and 5-HT2A antagonists, inverse agonists or partial agonists
US8304431B2 (en) * 2003-12-02 2012-11-06 Pharmaneuroboost N.V. Use of D4 and 5-HT2A antagonists, inverse agonists or partial agonists
US7884096B2 (en) * 2003-12-02 2011-02-08 Pharmaneuroboost N.V. Method of treating mental disorders using of D4 and 5-HT2A antagonists, inverse agonists or partial agonists
JP2009511606A (ja) 2005-10-14 2009-03-19 ハー・ルンドベック・アクチエゼルスカベット エスシタロプラムおよびブプロピオンの低用量の併用を用いる中枢神経系障害の治療方法
US20070134322A1 (en) * 2005-12-14 2007-06-14 Forest Laboratories, Inc. Modified and pulsatile release pharmaceutical formulations of escitalopram
FR2912057B1 (fr) * 2007-02-07 2009-04-17 Sanofi Aventis Sa Composition pharmaceutique contenant en association le saredutant et un inhibiteur selectif de la recapture de la serotonine ou un inhibiteur de la recapture de la serotonine/norepinephrine
TW200817003A (en) * 2006-07-31 2008-04-16 Sanofi Aventis Pharmaceutical composition comprising, in combination, saredutant and a selective serotonin peuptake inhibitor or a serotonin/norepinephrine reuptake inhibitor

Family Cites Families (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1143702A (zh) 1965-03-18
GB1526331A (en) 1976-01-14 1978-09-27 Kefalas As Phthalanes
US4439545A (en) 1981-11-19 1984-03-27 Societe D "Expansion Scientifique "Expansia" Acrylic copolymers of N-acryloylpolymethyleneimines or N-acryloyldialkylamides, N,N'-acryloyldiaminoalcanes and N-acryloylaminoacids (or esters) their preparation and use as cation exchangers
GB8419963D0 (en) 1984-08-06 1984-09-12 Lundbeck & Co As H Intermediate compound and method
GB8607313D0 (en) * 1986-03-25 1986-04-30 Ici Plc Pharmaceutical compositions
GB8814057D0 (en) 1988-06-14 1988-07-20 Lundbeck & Co As H New enantiomers & their isolation
US4902710A (en) 1988-12-14 1990-02-20 Eli Lilly And Company Serotonin and norepinephrine uptake inhibitors
US5114976A (en) 1989-01-06 1992-05-19 Norden Michael J Method for treating certain psychiatric disorders and certain psychiatric symptoms
US4962128A (en) 1989-11-02 1990-10-09 Pfizer Inc. Method of treating anxiety-related disorders using sertraline
US5296507A (en) * 1990-09-06 1994-03-22 H.Lundbeck A/S Treatment of cerbrovascular disorders
DK213290D0 (da) 1990-09-06 1990-09-06 Lundbeck & Co As H Treatment of cerebrovascular disorders
US5708035A (en) 1991-02-04 1998-01-13 Sepracor Inc. Methods of use and compositions of R(-) fluoxetine
AU1919592A (en) 1991-04-16 1992-11-17 National Institutes Of Health Method of treating trichotillomania and onychophagia
EP0612242B1 (en) 1991-11-15 2003-07-09 Sepracor Inc. Use of the pure s(+) isomer of fluoxetine for the preparation of a medicament against migraine headache
EP0714663A3 (en) * 1994-11-28 1997-01-15 Lilly Co Eli Potentiation of drug responses by serotonin 1A receptor antagonists
US5627196A (en) * 1995-01-17 1997-05-06 Eli Lilly And Company Compounds having effects on serotonin-related systems
AU4918796A (en) * 1995-02-10 1996-08-27 Eli Lilly And Company Methods of treating or preventing psychiatric disorders
US5554383A (en) 1995-04-06 1996-09-10 Trustees Of Tufts College Veterinary method for clinically modifying the behavior of dogs exhibiting canine affective aggression
SE9501567D0 (sv) 1995-04-27 1995-04-27 Astra Ab A new combination
EP0759299B1 (en) 1995-08-16 2000-04-26 Eli Lilly And Company Potentiation of serotonin response
US5846982A (en) * 1996-06-14 1998-12-08 Eli Lilly And Company Inhibition of serotonin reuptake
US5912256A (en) * 1996-06-20 1999-06-15 Eli Lilly And Company Compounds having effects on serotonin-related systems
US5747494A (en) * 1996-06-28 1998-05-05 U C B S.A. Pharmaceutical compositions for the treatment of depressive disorders
US5958429A (en) 1996-08-16 1999-09-28 Eli Lilly And Company Potentiation of serotonin response
ZA977967B (en) 1996-09-23 1999-03-04 Lilly Co Eli Combination therapy for treatment of psychoses
US5776969A (en) * 1997-02-27 1998-07-07 Eli Lilly And Company Treatment of sleep disorders
US6069177A (en) 1997-07-08 2000-05-30 The Hong Kong University Of Science And Technology 3-Hydroxy-propanamine derived neuronal reuptake inhibitors
SE9703379D0 (sv) * 1997-09-18 1997-09-18 Astra Ab New compounds
SE9703375D0 (sv) 1997-09-18 1997-09-18 Astra Ab A new combination
SK283907B6 (sk) * 1997-11-11 2004-04-06 H. Lundbeck A/S Spôsob výroby citalopramu a medziprodukty
EP0957099B1 (en) * 1998-04-15 2002-11-20 Pfizer Products Inc. Heterocyclic carboxamides
EP1100501A4 (en) * 1998-06-30 2002-12-04 Lilly Co Eli PYRROLIDINE AND PYRROLIDINE DERIVATIVES INFLUENTING THE SYSTEMS ASSOCIATED WITH SEROTONIN
EP1096926B1 (en) 1998-07-13 2007-02-28 Nps Pharmaceuticals, Inc. Methods and compounds for treating depression
US6579899B1 (en) 1998-07-16 2003-06-17 Massachusetts Institute Of Technology Composition for treatment of stress
WO2000003701A1 (en) 1998-07-16 2000-01-27 Massachusetts Institute Of Technology Composition for treatment of stress
US6150376A (en) * 1998-08-05 2000-11-21 Georgetown University Bi- and tri-cyclic aza compounds and their uses
SE9803158D0 (sv) * 1998-09-16 1998-09-16 Astra Ab A new composition
SE9803157D0 (sv) 1998-09-16 1998-09-16 Astra Ab A new composition
BR9915158B1 (pt) * 1998-10-20 2012-02-22 método para preparação de citalopram, e, compostos da fórmula geral viii, ix e iv, ou qualquer de seus enantiÈmeros e sais com adição de ácido do mesmo.
AR021509A1 (es) * 1998-12-08 2002-07-24 Lundbeck & Co As H Derivados de benzofurano, su preparacion y uso
CZ296537B6 (cs) * 1999-04-14 2006-04-12 H. Lundbeck A/S Zpusob výroby citalopramu a meziprodukty
AR021155A1 (es) 1999-07-08 2002-06-12 Lundbeck & Co As H Tratamiento de desordenes neuroticos
US6333357B1 (en) 1999-11-05 2001-12-25 Be Able, Llc Behavior chemotherapy
UA77650C2 (en) 1999-12-06 2007-01-15 Lundbeck & Co As H Use of serotonin reuptake inhibitor in combination with deramcyclane
GB2357762B (en) * 2000-03-13 2002-01-30 Lundbeck & Co As H Crystalline base of citalopram
WO2001080845A2 (en) 2000-04-24 2001-11-01 Aryx Therapeutics (2-aminoethyl) oxime derivatives for the treatment of depression
JP2002361405A (ja) * 2000-09-25 2002-12-18 Showa Denko Kk 熱交換器の製造方法
CN1509169A (zh) * 2001-05-01 2004-06-30 H��¡�±������޹�˾ 对映体纯艾司西酞普兰的用途

Also Published As

Publication number Publication date
IL170193A (en) 2010-04-29
AU2005202686A1 (en) 2005-07-14
DK1200081T3 (da) 2006-12-27
US6960613B2 (en) 2005-11-01
KR100604176B1 (ko) 2006-07-25
EP1440690A2 (en) 2004-07-28
NO20020062D0 (no) 2002-01-07
CZ200270A3 (cs) 2002-04-17
MXPA01011626A (es) 2002-06-04
UA77645C2 (en) 2007-01-15
US7271194B2 (en) 2007-09-18
EP1200081B1 (en) 2006-09-20
CA2373757C (en) 2010-01-05
TR200402276T2 (tr) 2005-01-24
TWI232101B (en) 2005-05-11
AU2005202685B2 (en) 2009-01-15
ATE339955T1 (de) 2006-10-15
AU5806100A (en) 2001-01-30
TR200402275T2 (tr) 2005-03-21
AU782514B2 (en) 2005-08-04
CL2008003938A1 (es) 2009-05-22
JP4773011B2 (ja) 2011-09-14
PL352030A1 (en) 2003-07-28
CL2008003941A1 (es) 2009-05-22
BG106279A (bg) 2002-08-30
TR200200014T2 (tr) 2002-05-21
IL170194A (en) 2010-05-31
EP1200081A1 (en) 2002-05-02
ES2272298T3 (es) 2007-05-01
EA200200137A1 (ru) 2002-06-27
BG110467A (en) 2010-01-29
TR200402277T2 (tr) 2005-01-24
ZA200108856B (en) 2002-12-24
NO20100335L (no) 2002-01-07
DE60030861T2 (de) 2007-05-03
EP1440689A3 (en) 2004-08-25
IL170192A (en) 2010-04-29
IL146131A (en) 2007-02-11
US20070276035A1 (en) 2007-11-29
HUP0201791A2 (en) 2002-10-28
US20040029958A1 (en) 2004-02-12
BG110466A (en) 2010-01-29
CA2373757A1 (en) 2001-01-18
AR021155A1 (es) 2002-06-12
AU2005202685A1 (en) 2005-07-14
BG110468A (en) 2010-01-29
EA006555B1 (ru) 2006-02-24
EP1440690A3 (en) 2004-08-18
EP1440691A3 (en) 2004-08-25
CL2008003939A1 (es) 2009-06-05
CN1360501A (zh) 2002-07-24
US7265151B2 (en) 2007-09-04
HK1048069B (zh) 2005-12-16
HRP20010820A2 (en) 2003-08-31
CO5190674A1 (es) 2002-08-29
NO20020062L (no) 2002-01-07
SI1200081T1 (sl) 2007-02-28
BR0011578A (pt) 2002-03-26
CA2687394A1 (en) 2001-01-18
MY143278A (en) 2011-04-15
KR20020015346A (ko) 2002-02-27
NO329021B1 (no) 2010-07-26
MEP2508A (xx) 2010-02-10
DE60030861D1 (de) 2006-11-02
YU78701A (sh) 2004-03-12
HK1048069A1 (en) 2003-03-21
AU2005202684A1 (en) 2005-07-14
EP1440691A2 (en) 2004-07-28
EP1440689A2 (en) 2004-07-28
AU2008264182A1 (en) 2009-01-29
US20020086899A1 (en) 2002-07-04
US20040029957A1 (en) 2004-02-12
AU2008264188A1 (en) 2009-05-07
CA2687396A1 (en) 2001-01-18
AU2005202684B2 (en) 2009-01-15
CA2687392A1 (en) 2001-01-18
IS6137A (is) 2001-10-30
HUP0201791A3 (en) 2005-02-28
NO20100333L (no) 2002-01-07
WO2001003694A1 (en) 2001-01-18
AU2005202686B2 (en) 2009-01-15
JP2003504332A (ja) 2003-02-04
US20040029956A1 (en) 2004-02-12
SK82002A3 (en) 2002-07-02
PT1200081E (pt) 2007-01-31
CY1105806T1 (el) 2011-02-02
US20050101665A1 (en) 2005-05-12
NO20100334L (no) 2002-01-07
IL146131A0 (en) 2002-07-25
ME00032B (me) 2010-02-10

Similar Documents

Publication Publication Date Title
CN1198610C (zh) 神经紊乱的治疗
EA008373B1 (ru) Применение эсциталопрама для лечения расстройства, связанного с посттравматическим стрессом
Lightowler et al. At pharmacologically active doses chronic moclobemide lacks anxiolytic-like activity in the rat social interaction model
EA008372B1 (ru) Применение эсциталопрама для лечения расстройства, связанного с социальной тревогой

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CX01 Expiry of patent term
CX01 Expiry of patent term

Granted publication date: 20050427