CN100430066C - 用于烟草依赖性和戒断治疗的化合物 - Google Patents
用于烟草依赖性和戒断治疗的化合物 Download PDFInfo
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- CN100430066C CN100430066C CNB2003801085134A CN200380108513A CN100430066C CN 100430066 C CN100430066 C CN 100430066C CN B2003801085134 A CNB2003801085134 A CN B2003801085134A CN 200380108513 A CN200380108513 A CN 200380108513A CN 100430066 C CN100430066 C CN 100430066C
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- chemical compound
- adenosine
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- cytidine
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Abstract
本发明提供了治疗或抑制烟草或尼古丁惯用或依赖的方法，其包括给哺乳动物施用治疗有效量的包含胞嘧啶的化合物或包含胞苷的化合物、包含肌酸的化合物、包含腺苷、或能升高腺苷水平的化合物。
Description
背景技术
本发明涉及用于治疗或抑制烟草或尼古丁依赖性或惯用的方法。
对于患者、临床医师、以及进行护理的人而言，物质滥用病症存在独特的并发症。这些病症难以明确地进行诊断并会担心受到社会非难，并且缺少简单有效的疗法，所以常常导致病人不愿向健康专家透露他们的症状，从而导致了不利的社会和健康后果。在所有年龄和背景的人中都会发生物质滥用病症，例如烟草或尼古丁的使用或依赖性。
使用诸如烟草或尼古丁之类的物质常常使得对这些物质成瘾或产生依赖，从而引起许多有害的后果，包括临床毒性、组织损伤、身体依赖性和戒断症状、以及维持社会和职业关系的能力受损。虽然物质滥用或依赖的病原学是未知的，但是已经假定诸如使用者的身体特性(例如遗传因素、年龄、体重)、个性、或社会经济等级之类的因素是决定因素。
迄今为止已经证明对这些病症而言还缺乏简单有效的药物治疗。向包括老年人和儿童在内的需要对烟草或尼古丁依赖或惯用进行治疗的所有人提供适于给药的药物疗法将是有益的。
发明概述
一般而言，本发明的特征在于通过给哺乳动物施用治疗有效量的包含胞苷、包含胞嘧啶、包含肌酸、包含尿苷、包含腺苷、或升高腺苷水平的化合物来治疗或抑制烟草或尼古丁依赖性或惯用的方法。本发明任何包含胞苷、包含胞嘧啶、包含肌酸、包含尿苷、包含腺苷、或升高腺苷水平的化合物都可以被单独给药。
在优选的实施方案中，包含胞苷的化合物是胞苷、CDP、或CDP-胆碱；包含胞苷的化合物包括胆碱；和哺乳动物是人类的儿童、青少年、成人、或老年人。在其它优选的实施方案中，该CDP-胆碱被口服给药并且该给药是长期的，例如在高于1、2、3、4、5、6、7、14、21、30、60、90、或180天的时期内或甚至在高于一年的时期内进行治疗。
在其它优选的实施方案中，还将脑磷脂(例如，卵磷脂)或脑磷脂前体(例如，脂肪酸或脂质)给药于所述哺乳动物。在其它优选的实施方案中，还给所述哺乳动物施用抗抑郁剂。
使用“烟草”时指的是任何形式的烟草，包括香烟、雪茄、和无烟烟草。
“滥用”指的是对物质的过度使用，特别是可能改变机体机能的使用。
“依赖”或“依赖性”指的是由于使用烟草或尼古丁而导致的或者至少部分是由其导致的表现出做决定的能力发生变化或降低的任何形式的行为。依赖性行为的典型形式可能表现为不爱社交或不适当的行为并且包括这些指向于希望、打算、获得、和使用烟草或尼古丁的行为。该术语还包括可能伴有或不伴有生理学上的依赖的对烟草或尼古丁的精神渴求、以及为了体验其精神作用或避免由于不使用其而引发的不适而连续或定期强迫性使用烟草或尼古丁的状态。依赖性形式包括习惯性，即，为了缓解压力和减轻情绪上的不适而对烟草或尼古丁有精神或心理依赖；耐受性，即，为了获得并维持所需的作用而增加剂量的渐近性需求；成瘾性，即，超过自愿控制的身体或生理学上的依赖；和了防止戒断症状而使用烟草或者尼古丁。依赖性可能受许多因素的影响，包括使用者的身体特征(例如，遗传因素、年龄、性别、体重)、个性、及社会经济等级。
“治疗”指的是将产生疾病、病理学情况、或病症的治愈、改善、或者预防的对患者进行的医学控制。该术语包括主动治疗，即，定向于除去所说疾病、病理学情况、或疾病的病因的治疗。此外，该术语还包括治标治疗，即，用来缓解症状而不是治愈所述疾病、病理学情况、或病症的治疗；预防治疗，即，用来预防所述疾病、病理学情况、或病症的治疗；和支持性疗法，即用来对用于改善疾病、病理学情况、或病症的另外的特定疗法进行补充的治疗。术语“治疗”包括对症治疗，即，定向于所说疾病、病理性情况、或病症的全部症状的治疗。
“抑制”指的是减少对烟草或尼古丁的欲望、需要、或使用数目。
“治疗有效量”指的是在烟草或尼古丁惯用或依赖性的治疗或抑制中足以产生恢复、治愈、预防、稳定、或改善作用的包含胞苷、包含胞嘧啶的化合物、包含尿苷的化合物、包含肌酸化合物、包含腺苷的化合物、或升高腺苷水平的化合物的数量。
“包含胞苷的化合物”指的是包括作为一种组分的胞苷、CMP、CDP、CTP、dCMP、dCDP、或dCTP的任何化合物。包含胞苷的化合物可以包括胞苷的类似物。优选的包含胞苷的化合物非限制性地包括CDP-胆碱和胞苷5′-二磷酸胆碱(通常被制备成胞苷5′-二磷酸胆碱[钠盐]并且也被称为胞磷胆碱)。
“包含胞嘧啶的化合物”指的是包括作为一种组分的胞嘧啶的任何化合物。包含胞嘧啶的化合物可以包括胞嘧啶的类似物。
“包含腺苷的化合物”指的是包括作为一种组分的腺苷的任何化合物。包含腺苷的化合物可以包括腺苷的类似物。
“升高腺苷水平的化合物”指的是能升高脑腺苷水平的任何化合物，例如可抑制或改变腺苷转运或代谢的化合物(例如潘生丁或S-腺苷甲硫氨酸)。
“包含尿苷的化合物”指的是包括作为一种组分的尿苷或UTP的任何化合物。包含尿苷的化合物可以包括尿苷的类似物，例如，三乙酰基尿苷。
“包含肌酸的化合物”指的是包括作为一种组分的肌酸的任何化合物。包含肌酸的化合物可以包括肌酸的类似物。
“磷脂”指的是包含磷的脂质，例如磷脂酸(例如卵磷脂)、磷酸甘油酯、鞘磷脂、和缩醛磷脂。“磷脂前体”指的是在磷脂的合成过程中被构建为磷脂的物质，例如，脂肪酸、甘油、或鞘氨醇。
“儿童或青少年”指的是未生长完全和发育成熟的个体。一般而言，儿童或青少年的年龄在二十一岁以下。
“老年人”指的是处生命的后期的个体。一般而言，老年人的年龄高于六十岁。
这里所用的化合物是相对无毒的，并且特定地，已经了解了CDP-胆碱、尿苷、和三乙酰基尿苷的哺乳动物药物代谢动力学并且其哺乳动物药物代谢动力学是已知的。因此，本发明提供了可能具有较少副作用并且可用于儿童和青少年、以及老年、或者由于存在身体健康状况而导致其健康受到损害的这些人。
从下面的说明书和权利要求来看，本发明的其它特征和优点将变得显而易见。
附图的简要说明
图1是表示胞磷胆碱对烟草应用情况的影响的图。
图2是说明CDP-胆碱的分子结构的图解。
本发明的详细描述
这里所描述的本发明的特征是用于治疗或抑制烟草或尼丁依赖或惯用的方法。
为此，本发明的特征是包含胞苷、包含胞嘧啶、包含尿苷、包含肌酸、包含腺苷、和升高腺苷水平的化合物用于缓解这些病症的症状的应用。一种优选的包含胞苷的化合物是CDP-胆碱(也被称为胞磷胆碱或CDP胆碱[钠盐])，一种优选的包含腺苷的化合物是S-腺苷甲硫氨酸(SAMe)，和一种优选的包含尿苷的化合物是三乙酰基尿苷。
所述包含胞苷、包含胞嘧啶、包含尿苷、包含肌酸、包含腺苷、或升高腺苷水平的化合物可以与是脑磷脂合成前体的其它化合物例如脂肪酸、脂质或卵磷脂共同给药。
烟草或尼古丁惯用或依赖
我们令人吃惊地发现CDP-胆碱可用于治疗烟草或尼古丁依赖或惯用，并且相信其它相关的化合物可能有类似的用途。图1的数据表明与接受安慰剂的人类个体的惯用相比，使用胞磷胆碱降低了对香烟的惯用(以每天抽的香烟的数量表示)。
包含胞苷和包含胞嘧啶的化合物
有用的包含胞苷或包含胞嘧啶的化合物可包括包含如下物质中的一种的任何化合物：胞嘧啶、胞苷、CMP、CDP、CTP、dCMP、dCDP、和dCTP。优选的包含胞苷的化合物包括CDP-胆碱和胞苷5′-二磷酸胆碱[钠盐]。提供包含胞苷和包含胞嘧啶的化合物的这种列表是为了进行举例说明，而不是要用其对本发明进行限制，并且上述化合物是可以通过商业途径获得的，例如可得自Sigma Chemical Company(St.Louis，MO)。
CDP-胆碱是在体内可以水解成其组分胞苷和胆碱的天然存在的化合物。CDP-胆碱是在一种由酶CPT：磷酸胆碱胞苷酰转移酶催化的可逆反应中由胞苷-5′-三磷酸盐和磷酸胆碱合成的，同时伴有无机焦磷酸盐的产生(Weiss，Life Sciences 56：637-660，1995)。CDP-胆碱可以以500mg长椭圆形药片的形式被获得来用于口服给药。每一片剂包含522.5mg CDP-胆碱钠，相当于500mg CDP-胆碱。还可以获得匹配的安慰剂片。活性片剂和安慰剂片剂中所包含的赋形剂有滑石粉、硬脂酸镁、胶体二氧化硅、氢化蓖麻油、羧甲基纤维素钠、和微晶纤维素。在图2中提供了CDP-胆碱[钠盐]的分子结构。
用于治疗或抑制烟草或尼古丁惯用或依赖的其它制剂可采用与可药用的稀释剂、载体、稳定剂、或赋形剂联用的包含胞嘧啶或包含胞苷的化合物的形式。
包含腺苷和升高腺苷水平的化合物
包含腺苷或升高腺苷水平的化合物也可提供有用的治疗。有用的包含腺苷或升高腺苷水平的化合物非限制性地包括包含下面的腺苷、ATP、ADP、或AMP中的一种的任何化合物。一种优选的包含腺苷的化合物是S-腺苷甲硫氨酸(SAMe)。
此外，已知这些化合物能通过其它机理增加腺苷水平。例如，许多已知化合物都可以抑制腺苷的摄取，包括丙戊茶碱(在US 5,919,789中进行了描述)。可以抑制腺苷摄取的其它已知化合物有EHNA。
可用于增加脑腺苷水平的其它有用化合物有这些可以抑制可分解腺苷的酶(例如腺苷脱氨基酶和腺苷激酶)的化合物。最后，还可以将包含腺苷或腺苷前体(其在体内以腺苷的形式被释放)的化合物进行给药。
包含尿苷的化合物
尿苷和包含尿苷的化合物能提供有效的治疗，这是因为这些化合物能转化成CTP(一种PC生物合成中的限速因子)(Wurtman等，Biochemical Biochemical Pharmacology 60：989-992，2000)。有用的包含尿苷的化合物非限制性地包括任何包含尿苷、UTP、UDP、或UMP的化合物。一种优选的包含尿苷的化合物是三乙酰基尿苷。尿苷和包含尿苷的化合物及类似物可以被人很好的耐受。
包含肌酸的化合物
肌酸和包含肌酸的化合物提供了有效的治疗，这是因为这些化合物能通过增加脑磷脂水平而升高ATP的水平。已知肌酸和包含肌酸的化合物在相对高的剂量下可以被人良好的耐受。
给药
用常规的药学实践来提供用来给药于患者的适宜制剂或组合物。优选口服给药，但是可以使用任何其它适宜的给药途径，例如胃肠外给药、静脉内给药、皮下给药、肌内给药、颅内给药、眶内给药、眼睛给药、心室内给药、囊内给药、椎管内给药、脑池内给药、腹膜内给药、鼻内给药、或气雾剂给药。治疗制剂可以是液体溶液或混悬液形式(如例如对于静脉内给药而言)；对于口服给药而言，这些制剂可以是液体、片剂、或胶囊形式；并且对于鼻内制剂而言，可以为粉末、滴鼻剂、或气雾剂形式。
例如在“Remington：The Science and Practice of Pharmacy”(第20版)A.R.Gennaro主编，2000 Lippincott，费城，PA中对现有技术中用于制备这些制剂的众所周知的方法进行了描述。用于胃肠外给药的制剂例如可以包含赋形剂、无菌的水、盐水、聚亚烷基二醇如聚乙二醇、植物来源的油类、或氢化萘。
如果需要的话，可以使用缓释或长期释放传递系统。可以用可生物相容的、可生物降解的丙交酯聚合体、丙交酯/乙交酯共聚物、或聚氧化乙烯-聚氧化丙烯共聚物来控制所说化合物的释放。其它可能有用的胃肠外传递系统包括乙烯-醋酸乙烯酯共聚物颗粒、渗透泵、可植入的输入系统、和脂质体。用于吸入的制剂可包含赋形剂例如乳糖，或者可以是包含例如聚氧化乙烯-9-月桂基醚、甘胆酸盐和脱氧胆酸盐的水溶液，或者可以是用于以滴鼻剂的形式被给药的油性溶液，或者可以为凝胶形式。
本发明中的化合物如CDP-胆碱优选地以至少500毫克每日两次的剂量通过口服途径被给药。口服给予的CDP-胆碱可被生物利用，99％以上的CDP-胆碱和/或其代谢物被吸收并且在粪便中被排泄的量小于1％。被口服或静脉内给药CDP-胆碱被迅速转化为两种主要的循环代谢产物--胆碱和胞苷。主要的排泄途径为肺(12.9％)和尿(2.4％)途径；其余剂量(83.9％)显然被代谢掉和保留在组织中。
一般而言，本发明中的化合物如CDP-胆碱、尿苷、UTP、肌酸、或SAMe以与所要达到的作用相一致的剂量被给药并且一般是以单位剂型的形式被给药的。所述剂量范围优选地为每天50mg至每天2000mg。所说化合物的精确剂量可能取决于例如，使用者的年龄和体重、给药途径、以及被治疗症状的严重程度和性质。一般说来，所选择的剂量应足以治疗或抑制烟草或尼古丁的惯用或依赖、或其一种或多种症状，同时不会产生显著的毒性或不希望出现的副作用。正如上面所指出的那样，对于大多数适应征而言，优选的给药途径是口服。
在CDP-胆碱的情况中，一直没有报道超剂量。CDP-胆碱毒性多为自身限定，临床前研究中的大量摄食表现出通常的胆碱能症状(流涎、流泪、排尿、排便、以及呕吐)。
与其它治疗剂的联合
本发明包含胞苷的化合物、包含胞嘧啶的化合物、包含尿苷的化合物、包含肌酸的化合物、包含腺苷的化合物、和升高腺苷水平的化合物可以以单一疗法的形式给药，可以彼此联合、或与用于治疗物质滥用病症的其它化合物联合给药，所述其它化合物包括用于治疗或抑制烟草或尼古丁惯用或依赖、或与生理学或心理学上的情况有关的其它情况的化合物。
本发明中的化合物可以与用于这些病症的目前治疗(包括兴奋剂和抗抑郁剂)的较低剂联合给药。例如，本发明中的化合物可同磷脂例如卵磷脂或同脑磷脂前体例如脂肪酸或脂质联合给药，或者可作为用于治疗物质滥用病症的标准治疗的辅助药物。
在一个特定的实施方案中，本发明中的化合物可与抗抑郁药、抗惊厥剂、抗焦虑药、抗蹂狂药、抗精神病药、抗强迫症药、镇静-催眠药、兴奋剂、或抗高血压药联用。这些药物的实例非限制性地包括抗焦虑药，阿普唑仑、盐酸丁螺环酮、利眠宁、盐酸利眠宁、二钾氯氮
、盐酸地昔帕明、地西泮、哈拉西泮、盐酸羟嗪、双羟萘酸羟嗪、劳拉西泮、甲丙氨酯、奥沙西泮、普拉西泮、马来酸丙氯拉嗪、丙氯拉嗪、乙二磺酸丙氯拉嗪、和马来酸三甲丙咪嗪；抗惊厥剂，异戊巴比妥、异戊巴比妥钠、卡马西平、利眠宁、盐酸利眠宁、二钾氯氮
地西泮、双丙戊酸钠、乙琥胺、乙苯妥英、加巴喷丁、拉莫三嗪、硫酸镁、美芬妥英、甲苯比妥、甲琥胺、甲乙双酮、戊巴比妥钠、苯乙酰脲、苯巴比妥、苯巴比妥钠、苯琥胺、苯妥英、苯妥英钠、扑米酮、司可巴比妥钠、三甲双酮、丙戊酸、和氯硝安定；抗抑郁药，盐酸阿米替林、阿莫沙平、安非他酮、盐酸氯丙咪嗪、盐酸地昔帕明、盐酸多塞平、氟西汀、氟伏沙明、盐酸丙咪嗪、双羟萘酸丙咪嗪、异卡波肼、拉莫三嗪、盐酸麦普替林、盐酸去甲替林、盐酸帕罗西汀、硫酸苯乙肼、盐酸普罗替林、盐酸舍曲林、硫酸反苯环丙胺、盐酸曲唑酮、马来酸曲米帕明、和盐酸文拉法辛；抗躁狂药，碳酸锂和枸橼酸锂；抗强迫症药，氟伏沙明和盐酸氯丙咪嗪；抗精神病药，马来酸醋奋乃静、盐酸氯丙嗪、泰尔登、盐酸泰尔登、氯氮平、癸酸氟奋乃静、庚酸氟奋乃静、盐酸氟奋乃静、癸酸氟哌啶醇、氟哌啶醇、乳酸氟哌啶醇、碳酸锂、枸橼酸锂、盐酸克塞平、琥珀酸克塞平、苯磺酸甲砜达嗪、盐酸吗茚酮、奋乃静、匹莫齐特、盐酸丙氯拉嗪、丙氯拉嗪、乙二磺酸丙氯拉嗪、盐酸丙嗪、利哌利酮、甲硫达嗪、盐酸甲硫达嗪、氨砜噻吨、盐酸氨砜噻吨、和盐酸三氟拉嗪(trifloperzine)；镇静-催眠药，异戊巴比妥、异戊巴比妥钠、阿普比妥、仲丁巴比妥、水合氯醛、利眠宁、盐酸利眠宁、二钾氯氮
、地西泮、苯海拉明、艾司唑仑、乙氯维诺、盐酸氟西泮、格鲁米特、盐酸羟嗪、双羟萘酸羟嗪、劳拉西泮、盐酸左美丙嗪、盐酸咪达唑仑、非处方药、奥沙西泮、戊巴比妥钠、苯巴比妥、苯巴比妥钠、夸西泮、司可巴比妥钠、替马西泮、三唑仑、和酒石酸唑吡坦；兴奋剂，硫酸右旋苯丙胺、盐酸去氧麻黄碱、盐酸哌甲酯、和匹莫林；和抗高血压药，可乐定。
其它实施方案
如果各独立的公开物或专利申请被特定和单独表明在这里被引入作为参考，则本说明书中所提及的所有公开物、专利和专利申请在这里都被引入在相同程度上作为参考。
虽然已经用特定的实施方案对本发明进行了描述，但是应当清楚的是，能对其进行进一步改变，一般而言，按照本发明的原则，本发明将覆盖本发明的任何变型、应用、或适应性改变并且包括得自本公开物的在本发明所属现有技术的已知或常规实践范围内并可用于这里上述的必要特征的该类偏离，并且该类偏离都在所附权利要求的范围内。
其它实施方案位于权利要求的范围内。
Claims (5)
1.CDP-胆碱在制备用于治疗或抑制哺乳动物烟草或尼古丁依赖或惯用的药物中的应用。
2.如权利要求1所述的应用，其中所述药物呈口服给药剂型。
3.如权利要求1所述的应用，其中所述哺乳动物是人。
4.如权利要求3所述的应用，其中所述人是儿童或青少年。
5.如权利要求3所述的应用，其中所述人是老年人。
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| WO2003082211A2 (en) * | 2002-03-27 | 2003-10-09 | The Regents Of The University Of California | Synergy of dopamine d2 and adenosine a2 receptors activates pka signaling via beta/gamma dimers |
| CN100563660C (zh) * | 2002-12-20 | 2009-12-02 | 麦克莱恩医院 | 用于正常化睡眠/觉醒周期的化合物 |
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- 2003-11-06 MX MXPA05004866A patent/MXPA05004866A/es active IP Right Grant
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5409946A (en) * | 1991-05-29 | 1995-04-25 | Abbott Laboratories | Isoxazole, isothiazole and pyrazole compounds that enhance cognitive function |
| US5472958A (en) * | 1994-08-29 | 1995-12-05 | Abbott Laboratories | 2-((nitro)phenoxymethyl) heterocyclic compounds that enhance cognitive function |
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| Publication number | Publication date |
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| NO333979B1 (no) | 2013-11-04 |
| NO20052347L (no) | 2005-06-06 |
| US20040167093A1 (en) | 2004-08-26 |
| CA2503286A1 (en) | 2004-05-27 |
| US7053064B2 (en) | 2006-05-30 |
| AU2003291368A1 (en) | 2004-06-03 |
| AU2003291368A8 (en) | 2004-06-03 |
| RU2329811C2 (ru) | 2008-07-27 |
| WO2004043229A2 (en) | 2004-05-27 |
| RU2005117631A (ru) | 2006-01-20 |
| US7601701B2 (en) | 2009-10-13 |
| CA2503286C (en) | 2011-08-30 |
| BR0316054A (pt) | 2005-09-20 |
| JP4667041B2 (ja) | 2011-04-06 |
| UA83011C2 (ru) | 2008-06-10 |
| US20060217344A1 (en) | 2006-09-28 |
| PT1565055E (pt) | 2013-09-16 |
| EP1565055B1 (en) | 2013-06-12 |
| WO2004043229A3 (en) | 2004-08-26 |
| JP2006508129A (ja) | 2006-03-09 |
| ES2427347T3 (es) | 2013-10-30 |
| EP1565055A4 (en) | 2010-12-29 |
| HK1083732A1 (en) | 2006-07-14 |
| EP1565055A2 (en) | 2005-08-24 |
| CN1735343A (zh) | 2006-02-15 |
| MXPA05004866A (es) | 2005-11-04 |
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