CN1946292B - 减少共同滥用可能性的方法 - Google Patents
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Abstract
本发明提供了减少或消除哌甲酯药物的共同滥用的方法，包括确定被怀疑滥用或可能滥用哌甲酯药物和当与所述哌甲酯药物组合摄取时已知或被怀疑产生l-哌乙酯的物质的组合的患者或患者群，对所述患者或患者群提供基本上不含l-苏型哌甲酯的哌甲酯药物。
Description
技术领域
本发明涉及减少或消除哌甲酯药物与可滥用物质例如乙醇、可卡因、鸦片类物质或尼古丁的共同滥用(co-abuse)的方法。本发明还公开了减少在经历ADHD和其它给用哌酸酯类(phenidate)产品的病症的治疗的主体中的与哌酸酯类药物和诸如乙醇或其它中枢神经系统活性剂物质的共同给用有关的副作用的方法。
背景技术
哌甲酯已知被物质滥用者与乙醇和其它物质共同给用。在最新调查中，3％的大学生滥用哌甲酯。根据Teter等人的Pharmacotherapy，2003；23:609-17报道，98％的这些非法哌甲酯使用者还是酗酒者。Barrett等人的J.Clin Psychopharmacol，2002；22:633-4公开了当与乙醇相伴使用时，哌甲酯的口服形式比静脉内或鼻内给用形式变得更常见。对于哌甲酯和乙醇的共同滥用存在一些理论。它们包括精神作用的改变和增强、产生以欣快感和活力增加以及迷醉感减少为特征的理想作用，和被比作“低劣可卡因”或“饮食可乐”的经历。另一个理论是习惯于摄取兴奋剂用于治疗ADHD而长大的儿童很可能摄取违禁兴奋剂，诸如可卡因或methamphetarnine。因此需要这样的治疗，当哌甲酯与其它兴奋剂共同滥用时，该治疗不会产生上瘾的欣快感。
还需要减少在经历ADHD治疗的患者中的与哌酸酯类药物和诸如乙醇或其它中枢神经系统活性剂的物质的共同给用有关的副作用的方法。根据Sabri等人的Alcohol and Alcoholism，2003；38:352-6所述，患有儿童ADHD的主体中的乙醇依赖性开始较早并对治疗产生耐受性。共发病物质滥用在ADHD主体中更加流行。患有ADHD的成人已知具有共发病乙醇问题和物质使用病症的高风险。
使用哌酸酯类药物来治疗癌症相关性疲劳和认知障碍的主体还表现出共同滥用哌酸酯类的可能性。这些主体很可能摄取诸如鸦片类镇痛药的药物用于止痛。这些主体还更可能共同给用哌甲酯和乙醇。对于这些主体而言，需要使用与包含哌甲酯(特别是外消旋混合物)的其它制剂相比更安全的药物。
还发现使用哌酸酯类药物作为用于治疗疼痛状态的物质的助剂的主体将更可能摄取诸如鸦片类镇痛药的药物用于止痛，所述疼痛状态包括但不限于复杂性局部疼痛综合症、下腰痛、纤维肌痛、神经根病、周围神经病如糖尿病性神经病变、疱疹后神经痛、三叉神经痛。这些主体还更可能共同给用哌甲酯和乙醇。治疗神经病学或神经精神病学病症(包括但不限于中风、头创伤和抑郁症)的患者还更可能共同给用哌甲酯和乙醇。
Markowitz等人的J.Clin.Psychopharmacol，1999；19:362-6发现了在与乙醇共同摄取过量的哌甲酯之后，在血浆中发现了作为新的代谢物的哌乙酯(ethyl哌酸酯类)。许多哌甲酯产品，例如
和
带来了更大的共同滥用的可能性，因为哌乙酯是这些产品的代谢物。Markowitz等人的Drug Metabolism and Disposition，2000；28：620-5阐述了在共同给用单一剂量的哌甲酯和乙醇之后在人主体的血浆和尿中还检测到哌乙酯。哌乙酯已知具有多巴胺能活性。最近，Thomson等人的31st Annual Am.College of CHn.Pharmacol.MeetingAbstracts，2002发现，在共同给用外消旋哌甲酯和乙醇之后，l-哌甲酯进行立体选择性酯交换，变成l-哌乙酯。哌乙酯代谢物主要以l-异构体形式在尿中被排泄。哌甲酯主要以d-异构体形式被排泄。哌乙酯潜在地有助于共同滥用者中的欣快感和ADHD患者、癌症主体和患神经学或神经精神病学的病症主体中的副作用。
本发明的目的是提供治疗具有增加的共同滥用哌甲酯与违禁药物(illict drugs)诸如可卡因和甲基苯丙胺的可能性的患者的方法。本发明的目的还在于减少与哌酸酯类药物和乙醇、鸦片类物质或其它中枢神经系统活性剂的共同给用有关的可能的副作用。
本发明的另一个目的是在使用哌酸酯类药物来治疗癌症相关性疲劳和认知障碍的主体中减少与哌酸酯类药物和乙醇、鸦片类物质、尼古丁或其它中枢神经系统活性剂的共同给用有关的副作用。哌甲酯的苏型外消旋物(对映体对)是温和的中枢神经系统兴奋剂，其药理学活性在性质上与安非他明相似。已经假定与使用哌甲酯的dl-苏型外消旋物有关的不希望的副作用，包括厌食、体重减轻、失眠、眩晕和烦躁不安。另外，外消旋物是目录II的控制物质，其当经由静脉内或吸入或摄取给用时产生欣快感，因此引起高的滥用可能性。最近，已经发现外消旋物还可引起哌甲酯与其它兴奋剂的共同滥用。因此，需要给予不会干扰乙醇样外消旋哌甲酯且不产生副作用的组合物的治疗。
发明内容
本发明提供减少哌甲酯药物和当与所述哌甲酯药物组合摄取时被怀疑产生l-哌乙酯的物质的共同滥用的方法，包括确定被怀疑滥用或可能滥用所述组合的患者或患者群，并对所述患者或患者群提供基本上不含l-苏型哌甲酯的哌甲酯药物。哌甲酯药物可以包括dexmethylphenidate。本发明还提供减少哌甲酯药物和上瘾物质的组合的共同滥用的方法，包括确定被怀疑滥用或可能滥用所述组合的患者或患者群，并对患者或患者群提供基本上不含l-苏型哌甲酯的哌甲酯药物。
存在其中产生l-哌乙酯的物质的可能是乙醇的实施方案。还存在其中上瘾物质可能是可卡因或可卡因衍生物、鸦片类物质、乙醇、CNS活性剂或尼古丁的实施方案。可以理解上瘾物质已知产生影响精神活动的作用。药物可经口、静脉内、非肠道、气雾剂或气体悬浮剂、或皮下对患者或主体给用。这些剂型可包括至多约10毫克、5毫克或3毫克的基本上不含l-苏型哌甲酯的哌甲酯药物。该方法可包括约0.1毫克到约100毫克的所述的基本上不含l-苏型哌甲酯的哌甲酯药物。患者有时被怀疑患有ADD或ADHD。
本发明还公开了减少哌甲酯药物和当与哌甲酯药物组合摄取时被怀疑产生l-哌乙酯的物质的共同滥用的方法，包括确定被怀疑滥用或可能滥用所述组合的患者或患者群，并对所述患者或患者群提供基本上不含l-苏型哌甲酯的哌甲酯药物减少由摄取所述组合而产生的l-哌乙酯的量。
优选实施方案详述
根据本发明，提供了减少哌甲酯药物与上瘾或可滥用物质的共同滥用的方法。本发明的一个实施方案可优选包括确定被怀疑滥用或可能滥用哌甲酯药物和当与所述哌甲酯药物组合摄取时已知或被怀疑产生l-哌乙酯的物质的组合的患者或患者群，并对所述患者或患者群提供所述的基本上不含l-苏型哌甲酯的哌甲酯药物。
本发明的一些实施方案涉及减少或消除共同滥用的可能性或共同滥用本身的哌甲酯药物组合物。哌甲酯药物和其它可滥用物质诸如但不限于乙醇、可卡因或尼古丁的共同给用不产生与外消旋的哌甲酯或安非他明相同的精神作用。因此，含有本文公开的组合物的药物制剂将不可能被物质滥用者实施共同滥用。哌甲酯以如下所示的四种单独的光学异构体形式存在：
其中R2为苯基。临床上通常给用可药用盐。根据本发明还可给用其它的哌酸酯类药物，包括其中在上述结构中的甲基被C2-C4烷基取代且R2任选被C1-C4烷基取代的那些。
临床上，盐酸哌甲酯的苏型对映体对通常被给用以治疗ADD和ADHD。盐酸盐通常简称为“哌甲酯”。除非另外说明，本文中使用的术语“哌甲酯”广泛地包括哌甲酯及其可药用盐，包括盐酸哌甲酯。
虽然dl-苏型哌甲酯通常用于治疗应用，但是该外消旋物包括对该药物的药理学有效性显然无显著贡献的l-异构体，但是该l-异构体可能促使有关的副作用。因此希望给用基本上不含l异构体的剂型。目前已经发现类似的剂型可用于减少哌甲酯的共同滥用可能性。
在进一步的方面，本发明涉及减少由诸如但不限于乙醇、鸦片类镇痛药、尼古丁及其他中枢神经系统活性剂所加重的哌酸酯类药物的CNS副作用。更准确地说，包含dexmethylphenidate(又名哌甲酯，基本上不含l-异构体)的药物制剂是优选的治疗ADHD主体的模式，所述主体比普通人群具有更高的共发病酒精依赖性和更高的物质滥用病症风险。这些主体很可能摄取乙醇同时摄取ADHD药物。另外，dexmethylphenidate用于治疗癌症相关性疲劳和认知障碍或其它神经学或神经精神病学病症的患者的优选模式，所述患者更可能摄取乙醇并共同给用其它用于止痛的诸如鸦片类镇痛药的药物或其它中枢神经系统活性剂。
本发明的一些实施方案的药物制剂基本上不含l-苏型-哌甲酯和赤型-哌甲酯。在一些实施方案中，l-苏型-异构体的缺乏可有助于减少共同滥用可能性和副作用。本发明的实施方案当与乙醇共同给用时减少共同滥用可能性和减少副作用。可以理解，有若干理论可说明这一结果。一个理论可能是dexmethylphenidate制剂基本不含l-苏型-哌甲酯和赤型-哌甲酯。
本发明的药物制剂当与其它上瘾物质共同滥用时不产生欣快感。本发明的一个特征是该药物在摄取乙醇或摄取诸如鸦片类镇痛药的药物的ADHD或癌症患者中不产生副作用。
外消旋哌甲酯和乙醇的共同给用已知在人中产生影响精神活动的作用。这些副作用潜在地是由l-哌乙酯代谢物的产生所致。本发明的一个优点是dexmethylphenidate和乙醇的共同给用不会产生这些作用。本发明的一些实施方案和减少外消旋哌甲酯与乙醇的共同滥用的类似方法之间的区别是dexmethylphenidate基本上不含l-异构体。因此，不形成l-哌乙酯代谢物。所述l-哌乙酯可能对欣快感和副作用有贡献。
本发明的方法可具有多个针对本领域技术人员的特定需要的实施方案。在一些方法中，对患者提供或给用的药物包括具有至多约10毫克的基本上不含l-苏型哌甲酯的dexmethylphenidate的药物单位剂型。在其它实施方案中，该药物包括至多约5毫克的dexmethylphenidate或至多约3毫克的所述dexmethylphenidate，二者基本上不含l-苏型哌甲酯。在一些其它实施方案中，单位剂型可能具有约0.1毫克到约100毫克或更大的dexmethylphenidate的差异，然而具有减少的共同滥用作用。
进行治疗的患者可被提供或给用本发明的剂型，经口、静脉内、非肠道、气雾剂或气体悬浮剂或透皮途径进行。经口给用可通过胶囊或片剂进行。
实施例
主体：保持8只Sprague-Dawley大鼠在限量饲养方案下以保持它们的体重在375-425克的范围内。
仪器：在市售的含有声光渐变小室的双杆大鼠自发反应室内进行实验。该室装备有小球分配器，用于分配45毫克的小球。当实验阶段在进行时发出刺激光信号。
训练：使用已经过训练以判别共同给药的乙醇/可卡因与盐水的主体。大鼠在杠杆式平板机上进行每天30分钟的食物强化训练。在训练期间，每个杆结合有在10％w/v乙醇中的0.75毫克/千克的可卡因或结合有盐水注射剂(训练课前，i.p.15分钟)。对于每次训练，主体学习判别给用那个注射剂以判断那个杆是正确的。训练持续进行直到主体在每次训练课上都从正确的杆上开始并连续四个训练课都是如此。
试验：每周进行两次一般性试验。在实验阶段之间，对动物提供使用乙醇/可卡因和盐水注射剂的连续训练。在试验训练阶段，强化对两个杆的应答。使用在10％w/v乙醇中的0.75毫克/千克可卡因和盐水的试验在各个剂量-反应曲线测定的开始时进行。获得每个试验药物的完整剂量-反应曲线。实验注射剂在实验阶段开始之前15分钟i.p.给用。实验使用以下三种与10％w/v乙醇的共同给药的药物进行：HCldexmethylphenidate(d-MPH)、d，l-哌甲酯HCl(d，l-MPH)和可卡因。通过将实验物质溶于10％w/v乙醇中制备实验溶液，得到1毫升/千克的注射剂。在训练阶段和试验阶段开始之前15分钟i.p.给用。
结果：乙醇/可卡因样差别性激励作用的程度以在试验阶段期间在训练阶段期间结合有乙醇/可卡因的杆上的反应百分比表示。计算每个大鼠的这些值并计算每个组的平均值。与乙醇/可卡因的情况一样，乙醇/d，l-MPH在一个或多个剂量下产生100％的乙醇/可卡因-杆反应速率，而不减少与盐水对照实验阶段中的大鼠相比的反应速率。乙醇/d，l-MPH与乙醇/可卡因相比对于差别性激励和反应速率作用是等效力的。乙醇/d-MPH是乙醇/d，l-MPH效力的一半。
Claims (7)
1.基本上不含l-苏型哌甲酯的哌甲酯药物在制备用于减少患者的哌甲酯药物和与所述哌甲酯药物组合摄取的乙醇的共同滥用的药物中的应用。
2.权利要求1的应用，其中所述哌甲酯药物可经口、静脉内、非肠道、气雾剂或气体悬浮剂、或皮下被提供。
3.权利要求2的应用，包括最多10毫克的哌甲酯药物。
4.权利要求2的应用，包括最多5毫克的哌甲酯药物。
5.权利要求2的应用，包括最多3毫克的哌甲酯药物。
6.权利要求2的应用，包括0.1毫克到100毫克的哌甲酯药物。
7.权利要求1的应用，其中所述患者患有或被怀疑患有ADD或ADHD。
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2004
- 2004-04-26 US US10/832,210 patent/US20050239830A1/en not_active Abandoned
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2005
- 2005-04-26 NZ NZ550585A patent/NZ550585A/en not_active IP Right Cessation
- 2005-04-26 AU AU2005237538A patent/AU2005237538B2/en not_active Ceased
- 2005-04-26 KR KR1020067024793A patent/KR20070004127A/ko not_active Ceased
- 2005-04-26 BR BRPI0510325-8A patent/BRPI0510325A/pt not_active IP Right Cessation
- 2005-04-26 MX MXPA06012348A patent/MXPA06012348A/es not_active Application Discontinuation
- 2005-04-26 WO PCT/US2005/014226 patent/WO2005105087A2/en active Application Filing
- 2005-04-26 CN CN200580013063XA patent/CN1946292B/zh not_active Expired - Fee Related
- 2005-04-26 CA CA002564604A patent/CA2564604A1/en not_active Abandoned
- 2005-04-26 JP JP2007510875A patent/JP2007534763A/ja active Pending
- 2005-04-26 EP EP05738790A patent/EP1755393A4/en not_active Withdrawn
- 2005-04-26 KR KR1020137007346A patent/KR20130041359A/ko not_active Ceased
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2006
- 2006-10-17 IL IL178683A patent/IL178683A0/en unknown
- 2006-10-24 ZA ZA200608838A patent/ZA200608838B/en unknown
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2008
- 2008-11-12 US US12/269,471 patent/US20090062336A1/en not_active Abandoned
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2012
- 2012-02-10 US US13/370,663 patent/US20120136028A1/en not_active Abandoned
-
2013
- 2013-02-13 US US13/765,994 patent/US20130158073A1/en not_active Abandoned
Non-Patent Citations (1)
| Title |
|---|
| Thomson MR et al..Enantioselective transesterification of methylphenidate to ethylphenidate after coadministration with ethanol.《Journal of clinical pharmacology》.2002,第42卷(第9期), * |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2005237538B2 (en) | 2011-01-06 |
| KR20130041359A (ko) | 2013-04-24 |
| WO2005105087A3 (en) | 2006-10-12 |
| WO2005105087A2 (en) | 2005-11-10 |
| IL178683A0 (en) | 2007-02-11 |
| US20090062336A1 (en) | 2009-03-05 |
| US20130158073A1 (en) | 2013-06-20 |
| EP1755393A4 (en) | 2009-05-06 |
| US20050239830A1 (en) | 2005-10-27 |
| MXPA06012348A (es) | 2007-04-19 |
| AU2005237538A1 (en) | 2005-11-10 |
| BRPI0510325A (pt) | 2007-10-23 |
| CN1946292A (zh) | 2007-04-11 |
| CA2564604A1 (en) | 2005-11-10 |
| ZA200608838B (en) | 2008-05-28 |
| KR20070004127A (ko) | 2007-01-05 |
| EP1755393A2 (en) | 2007-02-28 |
| NZ550585A (en) | 2010-09-30 |
| US20120136028A1 (en) | 2012-05-31 |
| JP2007534763A (ja) | 2007-11-29 |
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