CN1271278A - 行为障碍的治疗方法 - Google Patents
行为障碍的治疗方法 Download PDFInfo
- Publication number
- CN1271278A CN1271278A CN98809440A CN98809440A CN1271278A CN 1271278 A CN1271278 A CN 1271278A CN 98809440 A CN98809440 A CN 98809440A CN 98809440 A CN98809440 A CN 98809440A CN 1271278 A CN1271278 A CN 1271278A
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- China
- Prior art keywords
- norepinephrine reuptake
- reuptake inhibitor
- tomoxetine
- treatment
- acid
- 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.)
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Abstract
将去甲肾上腺素重摄取抑制剂用于治疗行为障碍。
Description
本发明属于药物化学和精神病药物领域并提供了一种治疗称作行为障碍的精神性疾病的方法。
相当数量的儿童和青少年表现出忽视其他人基本权利的行为障碍,远远超出了所预计的个体发育的特异性。患有这些行为障碍的儿童和青少年按照社会上可接受的方式和遵守学校及家庭规则行动有相当的困难。行为障碍的病人一般表现出对人和动物的攻击性行为,他们欺骗、撒谎、偷窃、破坏其他人的财产、逃学、离家出走并具有各种另外的***症状。如果未经治疗,那么患有行为障碍的儿童和青少年一般会非常郁闷并且将面对困难的未来。他们不能满足成年人的要求、具有持续维持关系的难题、不能维系工作并经常违法和具有***行为。
当前用于治疗行为未来的疗法总体上不令人满意。据报导具有去甲肾上腺素能和多巴胺能作用的哌甲酯(RitalinTM)可诱导许多病人症状的改善(Shah等《儿童和青少年精神药理学杂志》4(4),255-261(1994))。然而,某些病人难以接受哌甲酯的给药,而另一些病人不能长期维持治疗。此外,由于在行为障碍病人中滥用药物的高度可能性,所以使用诸如哌甲酯这样的刺激剂是有问题的。Shah还证明某些病人从通过添加匹莫林即一种多巴胺重摄取抑制剂的强化哌甲酯疗法中获益。已经发现氟哌啶醇和碳酸锂在治疗行为障碍的攻击性症状中的实用性(Platt等《遗传性精神病学记录》41,657-662(1984)),但是两者均涉及不需要的副作用、包括对识别的反面作用。
对安全而有效地治疗行为障碍但没有当前疗法的缺陷的需求一直是精神病学团体所关注的。
本发明提供了一种治疗行为障碍的方法,该方法包括对需要这类治疗的病人给予有效量的去甲肾上腺素重摄取抑制剂的步骤。
包括在下面详细讨论的那些在内的许多化合物均为去甲肾上腺素重摄取抑制剂并且毫无疑问在未来还会确定出更多的化合物。在实施本发明的过程中,按照由Wong等在《药物开发研究》6,397(1985)中所述方案,要求包括表现出50%有效浓度为小于或等于约1000nM的重摄取抑制剂。用于本发明方法的去甲肾上腺素重摄取抑制剂的特征在于它们对抑制相对于在其它受体上起***或拮抗剂作用的能力的神经递质重摄取具有选择性。用于本发明方法的去甲肾上腺素重摄取抑制剂包括但不限于:
托莫西汀(tomoxetine)、即(R)-(-)-N-甲基-3-(2-甲基苯氧基)-3-***,通常将其以盐酸盐的形式进行给药。托莫西汀首先公开在美国专利#4,314,081中。本文所用的术语“托莫西汀”指的是该分子的任意酸加成的盐或游离碱。参见例如Gehlert等《神经科学通讯》157,203-206(1993)中对于托莫西汀作为去甲肾上腺素重摄取抑制剂的活性的讨论一文;
其中X是C1-C4的烷硫基且Y是C1-C2的烷基或其药物上可接受的盐。通式I的化合物公开在美国专利5,281,624、Gehlert,Robertson和Wong以及Gehlert等在《生命科学》55(22),1915-1920(1995)中的描述。在这些文献中提示出的化合物是大脑中去甲肾上腺素重摄取的抑制剂。还可以解释为所述的化合物以立体异构体的形式存在且由此它们不仅包括外消旋物而且包括分离的各种异构体以及各种异构体的混合物。例如,通式I的化合物包括下列典型的种类:
N-乙基-3-苯基-3-(2-甲硫基苯氧基)丙胺苯甲酸盐;
(R)-N-甲基-3-苯基-3-(2-丙硫基苯氧基)丙胺盐酸盐;
(S)-N-乙基-3-苯基-3-(2-丁硫基苯氧基)丙胺;
N-甲基-3-苯基-3-(2-乙硫基苯氧基)丙胺丙二酸盐;
(S)-N-甲基-3-苯基-3-(2-叔丁硫基苯氧基)丙胺萘-2-磺酸盐;
(R)-N-甲基-3-(2-甲硫基苯氧基)-3-***;
瑞波西汀(Reboxetine)(EdronaxTM)、即2-[α-(2-乙氧基)苯氧基苄基]吗啉,通常将其以外消旋物的形式进行给药。它首先公开在美国专利4,229,449中,该文献描述了它对于治疗抑郁症的实用性。瑞波西汀是一种选择性的去甲肾上腺素重摄取抑制剂。本文所用的术语“瑞波西汀”指的是作为外消旋物或对映体存在的该分子的任意酸加成的盐或游离碱;
duloxetine、即N-甲基-3-(1-萘基氧基)-3-(2-噻吩基)丙胺,通常将其以盐酸盐和以(+)对映体的形式进行给药。它首先公开在美国专利4,956,388中,该文献描述了它的高效能。本文所用的术语“duloxetine”指的是该分子的任意酸加成的盐或游离碱;
文拉法星(Venlafaxin)是文献中公知的,且其合成方法及其作为5-羟色胺和去甲肾上腺素吸收的抑制剂的活性公开在美国专利4,761,501中。在该专利中将文拉法星鉴定为化合物A;和
milnacipran、即(N,N-二乙基-2-氨甲基-1-苯基环丙烷甲酰胺)公开在美国专利4,478,836中,该文献的实施例4中描述了milnacipran的制备。该专利文献描述了这些化合物可作为抗忧郁药。Moret等在《神经药理学》24,1211-19(1985)中描述了它作为5-羟色胺和去甲肾上腺素重摄取的抑制剂的药理活性。
将上述与本发明所用化合物有关的所有美国专利文献引入本文作为参考。
优选的duloxetine肠溶配方是一种丸剂,它包括a)一种由duloxetine和药物上可接受的赋形剂组成的药芯;b)一种任意的分离层;c)一种包括羟丙基甲基纤维素乙酸琥珀酸(HPMCAS)和药物上可接受的赋形剂在内的肠溶层;d)一种任意的抛光层。下列实施例表示优选的这类配方的制剂。
实施例
10mg duloxetine基质/胶囊
所用物质表
珠蔗糖-极品淀粉20-25目 60.28mgduloxetine层duloxetine 11.21 羟丙基甲基纤维素 3.74分离层羟丙基甲基纤维素 2.51蔗糖 5.00滑石,500目 10.03肠溶层HPMCAS,LF级,Shin-Etsu Chemical Co., 25.05Tokyo,Japan柠檬酸三乙酯 5.00滑石,500目 7.52抛光层羟丙基甲基纤维素 8.44二氧化钛 2.81滑石 微量
141.60mg
通过在将duloxetine悬浮于4%w/w的羟丙基甲基纤维素水溶液中并用CoBall Mill(Fryma Mashinen AG,Rheinfelden,Switzerland)型MS-12研磨所述的悬浮物来制备duloxetine层。将带有Wurster柱的流化床干燥器用于制备这种产物、批量大小为1.0kg。由4%w/w的羟丙基甲基纤维素水溶液来添加分离层,其中还溶有蔗糖。
为了制备包肠溶衣的悬浮液,将纯化水冷却至10℃并添加和分散或溶解聚山梨醇酯、柠檬酸三乙酯和硅氧烷乳浊液。然后添加HPMCAS和滑石并搅拌至获得均匀体系为止,且通过添加氢氧化铵来完全中和HPMCAS直到将所述聚合物溶液中和完全为止。向这种悬浮液中添加羧甲基纤维素水溶液(0.5%w/w)并剧烈掺合。在包衣过程中将肠溶悬浮液维持在20℃。然后以约15ml/分钟的喷射速率将肠溶悬浮液添加到Wurster柱内部分完整的丸粒中,保持入口气温在约50℃。当将肠溶悬浮液添加完全时,在50℃下于Wurster中干燥产物并在60℃下于干燥室内的托盘上干燥3小时。接着涂布抛光层,它由含有二氧化钛和丙二醇作为增塑剂的4.5%w/w羟丙基甲基纤维素溶液组成。在流化床干燥器内使丸粒完全干燥且然后将它们填入3号明胶胶囊。
尽管将具有去甲肾上腺素重摄取抑制作用的所有化合物用于本发明的方法,但是其中某些是优选的。优选的情况是,较之其它神经递质去甲肾上腺素重摄取抑制剂对去甲肾上腺素具有选择性。另外优选的情况是去甲肾上腺素重摄取抑制剂选自托莫西汀、瑞波西汀或通式I的化合物。特别优选的是去甲肾上腺素重摄取抑制剂选自托莫西汀、瑞波西汀或(R)-N-甲基-3-(2-甲硫基-苯氧基)-3-***。
本领域技术人员可以理解本发明中所用的大多数或所有的化合物能够形成盐且一般使用药物的盐的形式,这通常是因为它们比游离碱的形式更容易结晶化和纯化。在所有情况中,上述成盐的药物的应用是本说明书中所包括的、通常是优选的且它们的名称中包括所有化合物的药物上可接受的盐。
用于本发明的许多化合物是胺、且由此它们与大量无机或有机酸反应而生成药物上可接受的酸加成的盐。由于某些本发明化合物的游离胺在室温下一般是油状的,所以优选将所述的游离胺转化成易于控制和给药的它们的药物上可接受的酸加成的盐,因为后者在室温下通常是固体。经常用来形成这类盐的酸是无机酸诸如盐酸、氢溴酸、氢碘酸、硫酸、磷酸等以及有机酸诸如对甲苯磺酸、甲磺酸、草酸、对溴苯磺酸、碳酸、琥珀酸、柠檬酸、苯甲酸、乙酸等。这类因为上可接受的盐的实例因此为硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯乙酸盐、苯丙酸盐、苯丁酸盐、柠檬酸盐、乳酸盐、b-羟基丁酸盐、乙醇酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、扁桃酸盐等。优选的药物上可接受的盐是那些与盐酸形成的盐。
给药
在最终的分析中,本发明所用的药物的剂量必须由临床医师根据具体情况使用药物知识、结合如临床试验所确定的药物特性以及病人的特征包括除临床医师准备治疗病人疾病以外的疾病来确定。本文可以并将给出一般剂量以及某些优选的剂量。
托莫西汀:约5mg/天-约100mg/天;优选约5-约70mg/天;更优选约10-约60mg/天;且更优选约10-约50mg/天;
通式I的化合物:约0.01mg/kg-约20mg/kg;优选的每日剂量约0.05mg/kg-10mg/kg;较理想的是约0.1mg/kg-约5mg/kg;
瑞波西汀:约1mg-约30mg,1-4次/天;优选约5-约30mg/天,1次/天;
duloxetine:约1mg-约30mg,1次/天;优选约5-约20mg,1次/天;
文拉法星:约10mg-约150mg,1-3次/天;优选约25-约125mg,3次/天;和
milnacipran:约10mg-约100mg,1-2次/天;优选约25-约50mg,2次/天。
可得到所涉及的所有化合物的口服形式且一般通过口服给药,因此口服给药是优选的。然而,口服给药不是唯一的途径乃至唯一优选的途径。例如,经皮给药对于那些对口服药品健忘或脾气暴躁的病人来说是非常需要的。在特殊情况中,还可以通过经皮、静脉内、肌内、鼻内或直肠内途径将药物进行给药。给药途径可以以任意方式改变,它由药物的物理特性和为了病人和护理者的方便来决定。
对行为障碍的最佳描述是如下由美国精神病协会在DSM-III-R中公布的诊断标准(《精神错乱的诊断和统计手册》,第3修订版(1987))。
行为障碍的诊断标准
A.行为障碍持续至少6个月,在此期间至少存在下列3种情况:
(1)不与受害者面对面地偷窃1次以上(包括伪证)
(2)离家出走至少2次、而生活在双亲或双亲替代者家庭(或离家出走1次而没有回来)
(3)经常撒谎(避免***身体或性乱之外)
(4)有意地从事于周期性的暴力活动
(5)经常逃学(对于年龄较大者而言,逃离工作)
(6)破坏某些其他人的房屋、建筑或汽车
(7)有意地毁坏其他人的财产(周期性的暴力活动之外)
(8)以身体接触方式残忍地对待动物
(9)强迫他人与他或她进行性行为
(10)使用武器从事了一次以上的打斗
(11)经常引发打架
(12)与受害者面对面偷窃(例如抢劫、抢钱包、敲诈、武力盗取)
(13)以身体接触方式残忍地对待人
B.如果是18岁或18岁以上,那么不满足***人格障碍的标准。
已经将行为障碍分成三种诊断类别。将本发明的方法用于治疗任意属于这些诊断类别内的病人。在下面的段落中描述了DSM-III-R诊断代码和这些亚型中每一种的具体内容。
312.30 群体型
基本特征是可与主要以群体活动出现的行为同等的问题显著。身体攻击性行为可以或可不出现。
312.00 单独攻击型
基本特征是由人引发的身体攻击性行为显著,通常针对成年人和同等年龄的人(不以群聚活动方式出现)。
312.90 难以鉴别型
这是一种患行为障碍的儿童和青少年的亚型,他们具有不能被分类成单独攻击型或群聚型的混合临床特征。
患行为障碍的病人通常伴有注意力缺乏性功能亢进障碍、双极障碍和特殊的发育障碍。病人会从将去甲肾上腺素重摄取抑制剂用于改善行为障碍的症状中受益而与伴随的疾病无关。此外,患有行为障碍和注意力缺乏性功能亢进障碍的病人会通过本发明的方法受益于两种疾病症状的改善。
本发明的方法可有效地治疗儿童、青少年或成年患者并且在不同年龄段病人中症状或具体的治疗方式没有显著性差异。然而,通常对于本发明的目的来说,儿童指的是低于***年龄的病人,青少年指的是***年龄至约18岁年龄段的病人,而成年人指的是18岁或18岁以上的病人。
抑制作用或去甲肾上腺素的重摄取
通过Wong等在上述文献中所述的一般方法可以确定化合物抑制去甲肾上腺素重摄取的能力。
将重为150-250gm的Male Sprague-Dawley大鼠断头并立即取出大脑。将大脑皮质在含有0.32M蔗糖和10mM葡萄糖的9个体积的培养基中匀化。在以1000×g、10分钟和17,000×g、28分钟进行差速离心后分离突触体粗制备物。将最终的沉淀悬浮于相同培养基中并在冰中保存到在同一天内使用为止。
如下测定突触体的3H-去甲肾上腺素吸收量。在37℃下于1mLKrebs-碳酸氢盐培养基中将皮质突触体(相当于1mg的蛋白质)保温5分钟,所述的Krebs-碳酸氢盐培养基中还含有10mM葡萄糖、0.1mM异丙烟肼、1mM抗坏血酸、0.17mM EDTA和50nM 3H-去甲肾上腺素。立即用2mL冰冻的Krebs-碳酸氢盐缓冲液稀释所述的反应混合物并用一种细胞收集器(Brandel,Gaithersburg,MD)在真空中过滤。用约5mL冰冻的0.9%盐水将滤器冲洗两次并通过液体闪烁计数来估计3H-去甲肾上腺素的吸收量。将在4℃下的3H-去甲肾上腺素累积量看作背景并将其从所有测定值中扣除。要求抑制50% 3H-去甲肾上腺素累积量(IC50值)的测试化合物浓度通过线性回归分析来确定。
Claims (10)
1.一种治疗行为障碍的方法,包括对需要这类治疗的病人给予有效量的去甲肾上腺素重摄取抑制剂。
2.一种权利要求1的方法,其中所述的去甲肾上腺素重摄取抑制剂选自托莫西汀、瑞波西汀、duloxetine、文拉法星、milnacipran和通式I的化合物:
其中X是C1-C4的烷硫基且Y是C1-C2的烷基或其药物上可接受的盐。
3.一种权利要求2的方法,其中所述的去甲肾上腺素重摄取抑制剂是托莫西汀、瑞波西汀或通式I的化合物。
4.一种权利要求3的方法,其中所述的去甲肾上腺素重摄取抑制剂是托莫西汀。
5.一种权利要求3的方法,其中所述的去甲肾上腺素重摄取抑制剂是瑞波西汀。
6.一种权利要求3的方法,其中所述的去甲肾上腺素重摄取抑制剂是(R)-N-甲基-3-(2-甲硫基-苯氧基)-3-***。
7.一种权利要求1-6中任意一种的方法,其中治疗群体类型的行为障碍。
8.一种权利要求1-6中任意一种的方法,其中治疗单独攻击性类型的行为障碍。
9.一种权利要求1-6中任意一种的方法,其中治疗难以鉴别类型的行为障碍。
10.一种权利要求8、9或10的方法,其中所述的去甲肾上腺素重摄取抑制剂是盐酸托莫西汀。
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Publication number | Priority date | Publication date | Assignee | Title |
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CN105164227A (zh) * | 2013-04-30 | 2015-12-16 | 旭硝子株式会社 | 包含三氟乙烯的组合物 |
Families Citing this family (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2329665C (en) * | 1998-04-24 | 2007-09-04 | Scarista Limited | Treatment of depression and pharmaceutical preparations therefor |
US6500827B2 (en) * | 1998-05-08 | 2002-12-31 | Pharmacia & Upjohn Company | Drug combinations |
ES2246485T3 (es) | 1999-07-01 | 2006-02-16 | PHARMACIA & UPJOHN COMPANY LLC | (s,s)-reboxetina para tratar la incontinencia. |
EP1459751B1 (en) * | 1999-07-01 | 2005-09-14 | Pharmacia & Upjohn Company LLC | (S,S)-reboxetine for treating migraine headaches |
AU2005220235B2 (en) * | 1999-07-01 | 2007-05-10 | Pharmacia & Upjohn Company | Selective norepinephrine reuptake inhibitors and methods of using the same |
US6387403B1 (en) * | 1999-09-15 | 2002-05-14 | Alza Corporation | Dosage forms and methods for providing effective reboxetine therapy with once-a-day dosing |
US20050096396A1 (en) * | 2002-03-28 | 2005-05-05 | Emory University | Acute pharmacologic augmentation of psychotherapy with enhancers of learning or conditioning |
AU2002311784B2 (en) * | 2001-03-29 | 2007-11-22 | Michael Davis | Acute pharmacologic augmentation of psychotherapy with enhancers of learning or conditioning |
US6613763B2 (en) * | 2001-04-20 | 2003-09-02 | Mgi Applied Genomics | Use of molindone to treat oppositional defiant disorder and conduct disorder |
EP2275959A3 (en) * | 2001-07-11 | 2011-04-06 | CNS Response, Inc. | Method of screening a therapeutic agent for therapeutic effectiveness |
US6700018B2 (en) * | 2001-07-17 | 2004-03-02 | Mayo Foundation For Medical Education And Research | Amine compounds and inhibiting neurotransmitter reuptake |
US6602911B2 (en) | 2001-11-05 | 2003-08-05 | Cypress Bioscience, Inc. | Methods of treating fibromyalgia |
CA2475763A1 (en) * | 2002-02-12 | 2003-08-21 | Cypress Bioscience, Inc. | Methods of treating attention deficit/hyperactivity disorder (adhd) |
ES2399880T3 (es) * | 2002-03-15 | 2013-04-04 | Cypress Bioscience, Inc. | Milnaciprán para el tratamiento del síndrome del intestino irritable |
AU2003223579A1 (en) * | 2002-04-18 | 2003-11-03 | Pharmacia Corporation | Combinations of cox-2 inhibitors and other agents for the treatment of parkinson's disease |
PL375211A1 (en) * | 2002-06-17 | 2005-11-28 | Pharmacia Italia S.P.A. | Pharmaceutical salts of reboxetine |
US20040235925A1 (en) * | 2002-12-17 | 2004-11-25 | Pharmacia Corporation | Method for the treatment, prevention, or inhibition of a CNS disorder and/or pain and inflammation using a combination of duloxetine, venlafaxine or atomoxetine and a cyclooxygenase-2 selective inhibitor and compositions thereof |
US6943193B1 (en) * | 2003-01-21 | 2005-09-13 | Jordan A. Altabet | Method for treating sexual dysfunction |
FR2851163B1 (fr) * | 2003-02-14 | 2007-04-27 | Utilisation de l'enantiomere dextrogyre du milnacipran pour la preparation d'un medicament | |
EP1908461B9 (fr) * | 2003-02-14 | 2011-08-31 | Pierre Fabre Medicament | Utilisation de l'énantiomère (1S, 2R) du milnacipran pour la préparation d'un médicament |
CA2532349A1 (en) * | 2003-08-27 | 2005-03-10 | Eli Lilly And Company | Treatment of stuttering and other communication disorders with norepinephrine reuptake inhibitors |
AU2004305563C1 (en) | 2003-12-11 | 2011-07-07 | Sunovion Pharmaceuticals Inc. | Combination of a sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression |
AU2004312059A1 (en) * | 2003-12-31 | 2005-07-21 | Actavis Group Hf | Atomoxetine formulations |
EP1791806A4 (en) * | 2004-06-07 | 2008-02-20 | Mayo Foundation | AMINE COMPOUNDS AND NEUROTRANSMITTER RECOVERY INHIBITION |
US7994220B2 (en) * | 2005-09-28 | 2011-08-09 | Cypress Bioscience, Inc. | Milnacipran for the long-term treatment of fibromyalgia syndrome |
US20080031932A1 (en) * | 2006-08-04 | 2008-02-07 | Watson Laboratories, Inc. | Transdermal atomoxetine formulations and associated methods |
WO2009089479A2 (en) | 2008-01-09 | 2009-07-16 | Mayo Foundation For Medical Education And Research | Inhibiting neurotransmitter reuptake |
US20100069389A1 (en) * | 2008-09-06 | 2010-03-18 | Bionevia Pharmaceuticals, Inc. | Novel forms of reboxetine |
EP2496079A4 (en) | 2009-11-06 | 2014-05-14 | Pierre Fabre Médicament Sas | NOVEL (1S, 2R) -2- (AMINOMETHYL) -N, N-DIETHYL-1-PHENYLCYCLOPROPANECARBOXAMIDE CRYSTALLINE FORMS |
WO2014159251A2 (en) | 2013-03-14 | 2014-10-02 | Mayo Foundation For Medical Education And Research | Inhibiting neurotransmitter reuptake |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
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CA2061665C (en) * | 1991-02-25 | 2002-04-16 | Mark Mortensen Foreman | Treatment of lower urinary tract disorders |
DK0537915T3 (da) * | 1991-09-27 | 1995-11-27 | Lilly Co Eli | N-alkyl-3-phenyl-3-(2-alkylthiophenoxy)propylaminer som inhibitorer for epinephrin |
ZA93694B (en) * | 1993-02-01 | 1993-06-03 | Lilly Co Eli | Pharmaceutical treatments. |
CA2134038C (en) | 1994-06-16 | 1997-06-03 | David Taiwai Wong | Potentiation of drug response |
ZA958725B (en) | 1994-10-20 | 1997-04-16 | Lilly Co Eli | Treatment of disorders with duloxetine |
US5658590A (en) * | 1995-01-11 | 1997-08-19 | Eli Lilly And Company | Treatment of attention-deficit/hyperactivity disorder |
CA2227410A1 (en) * | 1995-07-24 | 1997-02-06 | Eli Lilly And Company | Treatment of attention-deficit/hyperactivity disorder |
US5696168A (en) * | 1995-07-24 | 1997-12-09 | Eli Lilly And Company | Treatment of attention-deficit/hyperactivity disorder |
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CA2304657A1 (en) | 1999-04-01 |
NO20001479L (no) | 2000-03-22 |
TR200000756T2 (tr) | 2000-09-21 |
WO1999015163A1 (en) | 1999-04-01 |
US6184222B1 (en) | 2001-02-06 |
HUP0004025A3 (en) | 2002-02-28 |
KR20010024219A (ko) | 2001-03-26 |
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UA57107C2 (uk) | 2003-06-16 |
AU740192B2 (en) | 2001-11-01 |
IL134718A0 (en) | 2001-04-30 |
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EA200000351A1 (ru) | 2000-10-30 |
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