CN100482221C - 奈福泮治疗恶心或呕吐的用途 - Google Patents
奈福泮治疗恶心或呕吐的用途 Download PDFInfo
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Abstract
本发明涉及奈福泮在制备用于治疗恶心、头晕、视力模糊和呕吐的药物中的用途。
Description
发明领域
本发明涉及已知化合物治疗呕吐及相关症状的用途。
发明背景
奈福泮是中枢作用的非麻醉性镇痛剂，与其它镇痛剂无结构相关性。奈福泮对动物疼痛模型和人类已经显示出能诱导抗伤害感受(Heel等人综述于Drugs 19(4)：249-67，1980)。然而，奈福泮在小鼠甩尾试验、大鼠热板试验或Randall-Selitto压力试验中无活性(Conway和Mitchell，Arch.Int.Pharmacodyn.Ther.226(1)：156-71，1977)，暗示了它的镇痛机制本质上不是鸦片样的或抗炎的。奈福泮的抗伤害感受不能被纳洛酮阻断，这进一步暗示了其镇痛作用不是通过鸦片受体。
用奈福泮的对映异构体进行的体外和体内研究已经显示，(+)-奈福泮比(-)-奈福泮具有更有效的镇痛以及多巴胺、去甲肾上腺素和5-羟色胺再摄取抑制的性质，效力的顺序是(+)-奈福泮>(±)-奈福泮>(-)-奈福泮(Fasmer等人，J.Pharm.Pharmacol.42(6)：437-8，1987；Rosland和Hole，J.Pharm.Pharmacol.42(6)：437-8，1990；Mather等人，Chirality 12(3)：153-9，2000)。Mather等人(2000)推断“...目前没有强制性基本原理来证明给予或监测(奈福泮的)各个对映异构体”。
当和吗啡一起给药进行患者-对照痛觉缺失试验时，奈福泮也已经显示出是鸦片不足的(Mimoz等人，Anaesthesia 56(6)：520-5，2001)。
奈福泮的常规释放制剂已经商业供给很多年了，用于治疗中度到重度疼痛。然而，奈福泮的短消除半衰期(四小时)意味着它在通常的给药期间(一日三次)很难维持镇痛效果。奈福泮的剂量增加引起了与镇痛有关的药物不良反应发生次数的增加，胃肠外给予治疗剂量的奈福泮以后观察到了对脉搏和血压的不利影响(Heel等人，1980)。当口服给予奈福泮时，不存在对心脏的变时性和离子化作用(Bhatt等人，Br.J.Clin.Pharmacol.11(2)：209-11，1981)。
恶心和呕吐是使用很多药物的副作用，包括那些用于治疗疼痛的药物。
发明概述
根据本发明，呕吐或相关症状可以使用奈福泮来治疗。已知奈福泮的副作用方面，令人惊奇地发现，外消旋奈福泮及其对映异构体能够预防或减轻由阿片样物质及其它已知的前催吐剂引起的呕吐。
优选实施方案的描述
正如此处所用的，“奈福泮”指的是式I化合物
及盐，例如盐酸盐、代谢产物及其前药，以及(+)和(-)对映异构体，其尽可能地是光学纯的。可能优选(+)-奈福泮，因为由相互作用引起的副作用较小。
根据本发明，奈福泮用于治疗恶心、头晕、视力模糊或呕吐，包括但不限于急性的、延迟的、手术后的、临终的(last-phase)和预期的呕吐。该症状可能由例如化学疗法、辐射、毒素、怀孕、戒酒、尼古丁戒断、药物戒断、前庭病症、运动、术后呕吐、外科手术、胃肠道梗阻、胃肠道运动减弱、痛经、内脏痛、偏头痛、颅内压增高、颅内压降低、抑郁或麻醉性镇痛剂引起。另外，奈福泮可以用于治疗由某些药物例如抗抑郁药(实例包括阿米替林、丙米嗪、地昔帕明、文拉法辛、西酞普兰、曲唑酮、帕罗西汀、奈法唑酮、氟西汀和(S)-西酞普兰)、抗惊厥药(实例包括拉莫三嗪、加巴喷丁和卡马西平)、抗精神病药(实例包括氯氮平、氯丙嗪、氟奋乃静、氟哌啶醇和洛沙平)、抗焦虑药(实例包括丁螺环酮和劳拉西泮)、抗帕金森药(实例包括阿扑吗啡、培高利特、左旋多巴、多巴胺、那高利特、溴隐亭和金刚烷胺)、CNS兴奋剂(实例包括右旋安非他明和哌甲酯)、鸦片(实例包括吗啡、芬太尼、丁丙诺啡、可待因、美沙酮、羟考酮、phenacozine和二醋吗啡)以及抗癌药(实例包括顺铂、阿地白介素、六甲蜜胺、卡铂、卡莫司汀、环磷酰胺、cytarbine、氨烯咪胺、放线菌素D、柔红霉素、多西紫杉醇、多柔比星、表柔比星、氟尿嘧啶、伊达比星、异环磷酰胺、irotecan、洛莫司汀、氮芥、美法仑、甲氨蝶呤、米托蒽醌、喷司他丁、丙卡巴肼和链佐星)引起的呕吐。
根据本发明，当患者还被给予了另一种抗催吐剂时，可以使用奈福泮。这些药剂包括吩噻嗪类、5HT3受体拮抗剂、多巴胺拮抗剂、抗胆碱能药、抗组胺药、组胺类似物、大麻素、皮质类固醇、GABA受体拮抗剂、NK1受体拮抗剂以及α2和α3肾上腺素受体拮抗剂。这类化合物的特殊实例有赛克利嗪、多拉司琼、格拉司琼、昂丹司琼、托烷司琼、大麻隆、scopolenine、cinnerizine、异丙嗪、倍他司汀、地塞米松、甲泼尼龙、甲氧氯普胺、氯丙嗪、奋乃静、丙氯拉嗪、硫乙拉嗪、氟哌利多、多潘立酮和氟哌啶醇。
可以使用任何适合的给药途径。例如，任何口服的、局部的、眼睛的、直肠的、阴道的、吸入及鼻内给药途径都是合适的。活性剂的剂量取决于疾病的性质和程度、患者的年龄和状况、以及本领域技术人员熟知的其它因素。通常剂量是10-100mg，每天给药一到三次。
本发明所基于的证据如下。
研究
将从Leeds大学获得的雄性雪貂(0.9-1.7kg)在22±1℃下成对圈养，能自由摄取食物(SDS Diet′C′(E)，Special Diet Services，UK)和水。它们在07:00到21:00之间开灯的人工光照条件下圈养。为了实验使用，将动物从它们的饲养笼中取出来，单独放到观察笼中。动物可以自由摄取水和食物。将动物分成每组4只动物的单独的组。
经过训练的技术员在整个实验过程中密切观察动物，以确保动物保持良好的健康状况。另外，用录像记录动物行为，用于过后分析呕吐(参见Rudd等人，1994)。呕吐是以有节律的腹部收缩为特征的，这种收缩与来自胃肠道的固体或液体物质经口排出(也就是呕吐)有关，与物质的经过(也就是作呕运动)无关。计算非常不同的腹部收缩次数。
将(+)-奈福泮溶于盐水，按1ml/kg的体积给药。普通盐水用作对照赋形剂注射剂。按5ml/kgi.p.的体积给予顺铂(顺铂无菌注射剂，浓度50mg/50ml；Onco-Tain：Faulding Pharmaceuticals PLC.Queensway，Royal Leamington Spa，Warwickshire，CV31 3RW，UK)。
在给予催吐剂量的吗啡(0.125mg/kgs.c.)之前一小时，腹膜内预先给予雪貂(n＝4)外消旋奈福泮(1、3和10mg/kgi.p.-附图1a)、(-)-奈福泮(10和30mg/kg-附图1b)或(+)-奈福泮(0.3、1和3mg/kg-附图1c)。给予吗啡后4小时期间记录观察，并对作呕和呕吐发生率进行评分。结果显示在图1中。
将(+)-奈福泮(3mg/kg)腹膜内给予雪貂(n＝4)每天三次(q8h)，在顺铂给药(5mg/kgi.p.)的前一天开始，持续到顺铂给药后三天。顺铂给药后72hr期间记录观察，并对作呕和呕吐发生率进行评分。结果显示在图2中。
Claims (8)
1.(+)-奈福泮在制备用于治疗选自恶心和呕吐的症状的药物中的用途。
2.根据权利要求1的用途，其中，症状是急性的、延迟的、手术后的、临终的或预期的呕吐。
3.根据权利要求1或2的用途，其中，症状与痛经、偏头痛、癌症或其它疼痛症状有关。
4.根据权利要求1或2的用途，其中，症状是由辐射、毒素、怀孕、戒酒、尼古丁戒断、药物戒断、前庭病症、运动、术后恶心、外科手术、胃肠道梗阻、胃肠道运动减弱、内脏痛或者颅内压增高或降低中的一种或多种引起的。
5.根据权利要求1或2的用途，其中，症状是由药物引起的。
6.根据权利要求5的用途，其中，症状是由化学疗法引起的。
7.根据权利要求5的用途，其中，症状是由鸦片样镇痛剂引起的。
8.根据权利要求7的用途，其中，症状是术后呕吐。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0213869.1 | 2002-06-17 | ||
| GBGB0213869.1A GB0213869D0 (en) | 2002-06-17 | 2002-06-17 | The treatment of pain |
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| Publication Number | Publication Date |
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| CN1668294A CN1668294A (zh) | 2005-09-14 |
| CN100482221C true CN100482221C (zh) | 2009-04-29 |
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| CNB038167050A Expired - Fee Related CN100482221C (zh) | 2002-06-17 | 2003-06-17 | 奈福泮治疗恶心或呕吐的用途 |
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| US (2) | US20060040905A1 (zh) |
| EP (2) | EP1513518A1 (zh) |
| JP (2) | JP2005533784A (zh) |
| CN (1) | CN100482221C (zh) |
| AU (2) | AU2003240113B2 (zh) |
| BR (1) | BR0311874A (zh) |
| CA (2) | CA2489315A1 (zh) |
| GB (1) | GB0213869D0 (zh) |
| IL (1) | IL165773A0 (zh) |
| MX (1) | MXPA04012826A (zh) |
| NO (1) | NO20045496L (zh) |
| NZ (1) | NZ537197A (zh) |
| PL (1) | PL374418A1 (zh) |
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| GB0330049D0 (en) * | 2003-12-24 | 2004-02-04 | Arakis Ltd | The treatment of neuropathic pain conditions |
| GB0408864D0 (en) * | 2004-04-21 | 2004-05-26 | Arakis Ltd | Novel benzoxazocines |
| GB0515703D0 (en) * | 2005-07-29 | 2005-09-07 | Arakis Ltd | Therapeutic use of nefopam |
| AU2008268463B2 (en) * | 2007-06-22 | 2015-03-05 | Eli Lilly And Company | Methods and compositions for treating disorders |
| GB0721013D0 (en) | 2007-10-25 | 2007-12-05 | Sosei R & D Ltd | New Salts |
| KR101621726B1 (ko) | 2008-05-27 | 2016-05-17 | 더 유니버시티 오브 멜버른 | 유스타키오관 기능장애 치료용 국소 약학적 조성물 |
| US20110092493A1 (en) * | 2008-09-24 | 2011-04-21 | Clark Levi | Dose-controlled transdermal promethazine compositions and methods of use |
| KR101779991B1 (ko) * | 2009-05-20 | 2017-09-19 | 인쎄름 (엥스띠뛰 나씨오날 드 라 쌍떼 에 드 라 흐쉐르슈 메디깔) | 병소성 전정 질환을 치료하기 위한 세로토닌 5-ｈｔ3 수용체 길항제의 용도 |
| CN102781442B (zh) * | 2009-12-15 | 2016-02-17 | 儿童医院 | 使用奈福泮化合物治疗瘢痕和β-联蛋白介导的疾病的方法 |
| NZ747201A (en) | 2016-04-14 | 2023-02-24 | Sensorion | (+)-azasetron for use in the treatment of ear disorders |
| US10736905B1 (en) | 2016-09-09 | 2020-08-11 | Shahin Fatholahi | Nefopam dosage forms and methods of treatment |
| US10736874B1 (en) | 2017-09-08 | 2020-08-11 | Shahin Fatholahi | Methods for treating pain associated with sickle cell disease |
| US11446311B2 (en) | 2017-09-08 | 2022-09-20 | Shahin Fatholahi | Methods for treating pain associated with sickle cell disease |
| WO2020224754A1 (en) * | 2019-05-06 | 2020-11-12 | Chemcom S.A. | Malodor counteracting composition and agent and the use thereof |
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| ATE283033T1 (de) * | 1998-07-24 | 2004-12-15 | Jago Res Ag | Medizinische aerosolformulierungen |
| US20020013331A1 (en) * | 2000-06-26 | 2002-01-31 | Williams Robert O. | Methods and compositions for treating pain of the mucous membrane |
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| MXPA04012826A (es) | 2005-03-31 |
| BR0311874A (pt) | 2005-05-10 |
| ZA200410102B (en) | 2006-07-26 |
| AU2003240113A1 (en) | 2003-12-31 |
| EP1513517A1 (en) | 2005-03-16 |
| NO20045496L (no) | 2005-01-12 |
| AU2003240113B2 (en) | 2006-11-16 |
| US20060063753A1 (en) | 2006-03-23 |
| CN1668294A (zh) | 2005-09-14 |
| PL374418A1 (en) | 2005-10-17 |
| WO2003105833A1 (en) | 2003-12-24 |
| JP2005533784A (ja) | 2005-11-10 |
| EP1513518A1 (en) | 2005-03-16 |
| CA2489315A1 (en) | 2003-12-24 |
| US20060040905A1 (en) | 2006-02-23 |
| IL165773A0 (en) | 2006-01-15 |
| AU2003277077B2 (en) | 2006-11-02 |
| AU2003277077A1 (en) | 2003-12-31 |
| CA2489306A1 (en) | 2003-12-24 |
| WO2003105832A1 (en) | 2003-12-24 |
| NZ537197A (en) | 2007-10-26 |
| GB0213869D0 (en) | 2002-07-31 |
| JP2005531612A (ja) | 2005-10-20 |
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