CN105263481A - 使用薄荷醇和/或冰素治疗或预防抑郁 - Google Patents
使用薄荷醇和/或冰素治疗或预防抑郁 Download PDFInfo
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- CN105263481A CN105263481A CN201480029644.1A CN201480029644A CN105263481A CN 105263481 A CN105263481 A CN 105263481A CN 201480029644 A CN201480029644 A CN 201480029644A CN 105263481 A CN105263481 A CN 105263481A
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Abstract
本发明提供了用于治疗或预防抑郁的组合物,所述组合物含有治疗有效量的选自薄荷醇、冰素及其组合的化合物。本发明还提供了治疗或预防抑郁的方法,所述方法包括施用这类组合物。
Description
背景
概括而言,本申请涉及用于预防或治疗抑郁的方法和组合物。更具体而言,本申请涉及包含薄荷醇或冰素(Icilin)中的至少一种的组合物,还涉及施用这类组合物的方法。
重度抑郁(severedepression)是一种长期的、复发性的疾病,其通常难以诊断。此外,许多患者患有轻度或中度严重性的抑郁。常规的抗抑郁药仍然具有许多阻碍有效治疗抑郁的限制。谷氨酸能系统可以是抗抑郁治疗的潜在靶标。谷氨酸拮抗剂抑制谷氨酸与NMDA受体结合,从而能避免Ca2+蓄积并因此能避免兴奋性中毒(excitotoxicity)。然而,谷氨酸拮抗剂的使用存在巨大障碍,因为治疗干扰标准条件下谷氨酸的正常作用。
对用于治疗或预防精神疾病和/或障碍、不显示出已知抗抑郁药的不良副作用的化合物存在需求。许多患者关注能最小化与高剂量药物相关的副作用和/或产生另外的临床益处的替代疗法。因此,对开发可用于治疗精神疾病/障碍、预防精神疾病/障碍例如抑郁的发生和稳定情绪的化合物以及药物组合物和/或膳食组合物存在原来越多的关注。
概述
本发明的发明人令人惊奇地、预料不到地发现,来自香料的几种活性化合物能抑制新皮质和杏仁核中的神经活动,所述化合物是瞬时感受器电位M8(transientreceptorpotentialM8,TRPM8)通道激动剂薄荷醇。虽然冰素的结构与薄荷醇无关,但是本发明的发明人发现了与TRPM8离子通道合成超激动剂冰素相同的作用。
因此,在一个一般性的实施方案中,本申请提供了用于治疗抑郁的方法。所述方法包括给具有抑郁的个体施用治疗有效量的选自薄荷醇、冰素及其组合的化合物。
在一个相关的实施方案中,所述抑郁选自单相抑郁(unipolardepression)、双相抑郁(bipolardepression)、急性抑郁、慢性抑郁、亚慢性抑郁(sub-chronicdepression)、精神抑郁症(dysthymia)、产后抑郁(postpartumdepression)、更年期抑郁症状(climactericdepressivesymptoms)、季节性情感障碍及其组合。
在一个相关的实施方案中,所述组合物被定期施用至少1年。所述组合物可以每天施用。
在一个相关的实施方案中,所述组合物选自药剂、食物产品和食物产品补充剂。
在另一个实施方案中,提供了用于预防抑郁的方法。所述方法包括给具有抑郁风险的个体施用治疗有效量的选自薄荷醇、冰素及其组合的化合物。
在一个相关的实施方案中,所述抑郁选自单相抑郁、双相抑郁、急性抑郁、慢性抑郁、亚慢性抑郁、精神抑郁症、产后抑郁、更年期抑郁症状、季节性情感障碍及其组合。
在一个相关的实施方案中,所述组合物被定期施用至少1年。所述组合物可以每天施用。
在一个相关的实施方案中,所述组合物选自药剂、食物产品和食物产品补充剂。
在另一个实施方案中,提供了用于治疗或预防抑郁的组合物。所述食物产品包含治疗有效量的选自薄荷醇、冰素及其组合的化合物。
在一个相关的实施方案中,所述组合物是药剂。
在一个相关的实施方案中,所述组合物是食物产品。所述食物产品可以包含选自蛋白质、碳水化合物、脂肪及其组合的组分。
在一个相关的实施方案中,所述组合物是食物产品补充剂。
本申请的一个优点是比谷氨酸拮抗剂更有效和/或更安全地预防或治疗抑郁。
本申请的另一个优点是在不干扰标准条件下谷氨酸的正常作用的情况下预防或治疗抑郁。
本申请的另一个优点是用能容易地且安全地用在食物产品中的化合物预防或治疗抑郁。
本申请的另一个优点是通过靶向于神经元放电的突触前阶段来预防或治疗抑郁。
本申请的另一个优点是通过靶向于神经元放电的突触前阶段、同时降低兴奋性中毒的可能性来预防或治疗抑郁。
本申请的另一个优点是用能在香料中发现的天然存在的化合物预防或治疗抑郁。
本申请的另一个优点是在具有可忍受的副作用或没有副作用的情况下预防或治疗抑郁。
另外的特征和优点如本文所述,并且可以从下面的详细描述和附图中变得显而易见。
附图简要说明
图1显示了能用在本申请的组合物的实施方案中的化合物的化学结构。
图2显示了在不存在(对照)和存在TRPM8配体(芳樟醇、冰素或薄荷醇)的情况下外侧杏仁核谷氨酸能神经元中(小鼠脑切片中)的全细胞电流钳记录图。
图3显示了在每个5min记录期间(洗脱10min)随着细胞外应用的gabazine(GABAA阻滞剂)的浓度增加外侧杏仁核谷氨酸能神经元中(小鼠脑切片中)的全细胞电流钳记录图。
图4显示了外侧杏仁核谷氨酸能神经元中(小鼠脑切片中)的全细胞电流钳记录图,其显示了增强的猝发(burst)细节。
图5显示了在每个5min记录期间(洗脱10min)随着细胞外应用的gabazine(GABAA阻滞剂)的浓度增加(同时在暴露于不同浓度的gabazine之前10分钟或在暴露于不同浓度的gabazine期间还细胞外应用250μM薄荷醇)外侧杏仁核谷氨酸能神经元中(小鼠脑切片中)的全细胞电流钳记录图。
详细描述
除非另有说明,否则本文所表达的所有百分比均是以占组合物的总重的重量计的。当提及pH时,数值对应于用标准设备在25℃测定的pH。除非上下文清楚地有相反表示,否则本申请以及所附的权利要求书中所用的单数形式“一种”、“一个”和“该”、“所述”包括所指物的复数。本文所用的“约”应理解为是指数字周围范围的数。此外,本文的所有数值范围均应理解为包括该范围内的所有整数或分数。本文所公开的食品组合物可以缺少本文未具体公开的任意要素。因此,“包含”包括“基本上由……组成”和“由……组成”。
作为非限制性实例,本文所用的“抑郁”包括单相抑郁、双相抑郁、急性抑郁、慢性抑郁、亚慢性抑郁、精神抑郁症、产后抑郁、更年期抑郁症状和季节性情感障碍。
“预防”包括降低抑郁的风险和/或严重性。术语“治疗”、“处理”和“缓解”包括预防性或防止性处置(预防所靶向的病理学病症或障碍和/或减缓其发展)和治愈性、治疗性或疾病改善性处置,包括治愈、减缓、减轻诊断的病理学病症或障碍的症状和/或阻止其进展的治疗措施;以及治疗有感染疾病风险的或疑似已经感染了疾病的患者和患病或已经被诊断为患有疾病或医学病症的患者。该术语不必然表示对个体治疗至完全恢复。术语“治疗”和“处理”还指维持和/或促进未患病、但可能易于发生不健康情况的个体的健康。术语“治疗”、“处理”和“缓解”还旨在包括加强或增强一种或多种主要的预防性或治疗性措施。术语“治疗”、“处理”和“缓解”还旨在包括疾病或病症的膳食控制或者用于预防或防止疾病或病症的膳食控制。治疗可以是患者-或医生-相关的。
本文所用的“治疗有效量”是在个体中预防缺陷、治疗疾病或医学病症的量,或更概括地是减轻症状、控制疾病进展或给个体提供营养、生理或医学益处的量。
“动物”包括、但不限于哺乳动物,其包括、但不限于啮齿动物、水生动物、家养动物例如狗和猫、农场动物例如绵羊、猪、牛和马、以及人。如果使用“动物”、“哺乳动物”或其复数形式,则这些术语也适用于能显示出或在传代的情况下显示出效果的任意动物。本文所用的术语“患者”应理解为包括接受或预期接受治疗、如本文所定义的治疗的动物、尤其是哺乳动物、更尤其是人。尽管术语“个体”和“患者”在本文中通常用于指人,但是本申请并不限于此。因此,术语“个体”和“患者”是指具有能受益于所述治疗的医学病症或处于其风险中的任意动物、哺乳动物或人。
本文所用的“食物产品”和“食品组合物”应理解为包含任意数量的任选的另外的成分,包括常规食品添加剂,例如一种或多种蛋白质、碳水化合物、脂肪、酸化剂、增稠剂、缓冲剂或用于pH调节的物质、螯合剂、着色剂、乳化剂、赋形剂、矫味剂、矿物质、渗透压调节剂(osmoticagent)、药学上可接受的载体、防腐剂、稳定剂、糖、甜味剂、组织形成剂和/或维生素。所述任选的成分可以以任意适合的量添加。
如上文所述,本发明的发明人令人惊奇地、预料不到地发现,来自香料的活性化合物—瞬时感受器电位M8(TRPM8)通道激动剂薄荷醇—能抑制新皮质和杏仁核中的神经活动。虽然冰素的结构与薄荷醇无关,但是本发明的发明人发现了与TRPM8离子通道合成超激动剂冰素相同的作用;然而,冰素在人和动物中均产生极端冷觉。这些天然化合物通过以下方式降低神经兴奋性:1)增加触发动作电位的阈值并且因此增加在新皮质中触发动作电位所需的电流的量;和2)中断更高刺激水平下的动作电位,其最可能与新皮质和外侧杏仁核中Na+通道的使用依赖性阻滞相关。这些活性化合物改变放电模式、尤其是更高刺激水平下的放电模式,其中动作电位(AP)振幅的进行性和显著性减小发生至AP的完全中断。
不希望受理论束缚,发明人认为,与神经保护性谷氨酸拮抗剂相比,所选择的香料活性化合物、即薄荷醇和冰素的潜在机制解决了两个主要问题:1)薄荷醇和冰素靶向于AP的突触前阶段,从而降低了活性并减少了谷氨酸释放,这显著降低了达到兴奋性中毒水平的可能性;和2)薄荷醇和冰素在高刺激情况下更强地起作用。与典型地抑制谷氨酸结合NMDA受体的谷氨酸拮抗剂不同,薄荷醇和冰素降低神经元活性并且靶向于放电的突触前阶段,以至于更早一步降低了兴奋性中毒的可能性。
因此,本申请所提供的组合物包含治疗有效量的薄荷醇或冰素中的至少一种。在一个实施方案中,通过给需要其的个体施用包含薄荷醇或冰素中的至少一种的组合物治疗或预防抑郁。例如,包含薄荷醇或冰素中的至少一种的组合物可以被施用于具有抑郁的个体以治疗所述抑郁。所述的抑郁可以是单相抑郁、双相抑郁、急性抑郁、慢性抑郁、亚慢性抑郁、精神抑郁症、产后抑郁、更年期抑郁症状、季节性情感障碍及其组合。在一个实施方案中,所述组合物被定期施用至少1年、优选至少2年、更优选至少3年、甚至更优选至少4年、最优选至少5年。
可以将薄荷醇和/或冰素各自以0.0015mg/kg体重-400mg/kg体重、优选0.1mg/kg体重-300mg/kg体重、更优选1.0mg/kg体重-200mg/kg体重、最优选10.0mg/kg体重-100mg/kg体重的日剂量施用于个体。例如,可以将薄荷醇和/或冰素各自以0.0015mg/kg体重-0.01mg/kg体重、0.01mg/kg体重-0.1mg/kg体重、0.1mg/kg体重-1.0mg/kg体重、1.0mg/kg体重-10.0mg/kg体重、10.0mg/kg体重-100.0mg/kg体重、100.0mg/kg体重-200.0mg/kg体重、200.0mg/kg体重-300.0mg/kg体重、或300.0mg/kg体重-400.0mg/kg体重的日剂量施用于个体。
包含薄荷醇或冰素中至少一种的组合物可以是药剂、食物产品或食物产品补充剂。所述补充剂可以是例如片剂、胶囊、锭剂(pastille)或液体的形式。所述补充剂可以进一步含有保护性亲水胶体(例如树胶、蛋白质、改性淀粉)、粘合剂、成膜剂、包囊剂/材料、壁/壳材料、基质化合物、包衣物料、乳化剂、表面活性剂、增溶剂(油、脂肪、蜡、卵磷脂等)、吸附剂、载体、填充剂、共用化合物、分散剂、湿润剂、加工助剂(溶剂)、流动剂(flowingagent)、味道掩蔽剂、增重剂(weightingagent)、胶冻剂(jellifyingagent)和成凝胶剂(gelformingagent)。所述补充剂还可以含有常规药物添加剂和佐剂、赋形剂和稀释剂,包括、但不限于水、任意来源的明胶、植物胶(vegetablegums)、木质素磺酸盐(ligninsulfonate)、滑石粉、糖、淀粉、阿拉伯胶、植物油、聚亚烷基二醇、矫味剂、防腐剂、稳定剂、乳化剂、缓冲剂、润滑剂、着色剂、湿润剂、填充剂等。
可以将补充剂作为可摄入的载体或支持物加入到消费者可接受的产品中。这类载体或支持物的非限制性实例有药物、食品组合物和宠物食品组合物。食品和宠物食品组合物的非限制性实例有奶、酸奶、凝乳、干酪、发酵乳、基于奶的发酵产品、基于发酵谷物的产品、基于奶的粉末、人乳、早产儿配方、婴儿配方、口服补充剂和管饲产品。
在一个实施方案中,将包含薄荷醇或冰素中至少一种的组合物施用于人。在一个供选的实施方案中,将包含薄荷醇或冰素中的至少一种的组合物施用于非人的动物、优选猫或狗。有利地,可以将所述组合物由其主人提供给伴侣动物。
实施例
下面的非限制性实施例提供了开发和支持使用薄荷醇和冰素治疗或预防神经变性障碍这一概念的科学数据。
用小鼠脑切片研究了薄荷醇、芳樟醇(另一种瞬时感受器电位M8(TRPM8)通道激动剂)和冰素的作用。杏仁体(amygdaloidcomplex)位于新皮质和杏仁核中的中颞叶内。杏仁体的外侧和基底外侧核接受来自皮质和丘脑结构的感觉信息,加工该信息,然后直接或通过基底核将该信息传递至中央核。为了对神经元活动进行实验分析,可以用电极电激发来自基底外侧杏仁体的突触响应,并且可以测定动作电位。
图2显示了不存在芳樟醇、薄荷醇或冰素的情况下(对照)的记录和存在芳樟醇、薄荷醇或冰素的情况下的记录。在高度去极化的膜电位(约-30mV)下施加2.5s的矩形脉冲。记录显示,在TRPM8配体存在下,在高度去极化水平下,钠快通道的失活比对照更迅速地发生,从而避免了进一步的神经元放电。
图3显示了在每个5min的记录期间(10min洗脱)增加细胞外应用的GABAA阻滞剂gabazine的浓度的记录。如所示的那样,由于大量的突触前放电,神经元自发地呈现动作电位猝发。图4描绘了增强的猝发之一的细节,并且显示在单个猝发中能观察到连续的动作电位。与图3相比,图5显示了在相同条件下的记录,即,在每个5min的记录期间(10min洗脱)增加细胞外应用的gabazine的浓度,不同的是在图5中,在暴露于不同浓度的gabazine之前10分钟以及在暴露于不同浓度的gabazine期间细胞外应用薄荷醇250μM。如图中所示,神经元显示完全不存在自发性猝发或者存在的自发性猝发大大减少(比较图5与图3)。
这些实验结果证实,薄荷醇和冰素增加了触发动作电位的阈值,并且因此增加了在新皮质中触发动作电位所需的电流量,并且还中断了在更高刺激水平下的动作电位。
应当理解的是,对本文所述的目前优选的实施方案的各种改变和变型对本领域技术人员而言将是显而易见的。可以在不脱离本发明的精神和范围并且不减少其预期优点的情况下进行这类改变和变型。因此这类改变和变型也被所附的权利要求涵盖。
Claims (15)
1.治疗抑郁的方法,其包括给具有抑郁的个体施用治疗有效量的选自薄荷醇、冰素及其组合的化合物。
2.权利要求1的方法,其中所述抑郁选自单相抑郁、双相抑郁、急性抑郁、慢性抑郁、亚慢性抑郁、精神抑郁症、产后抑郁、更年期抑郁症状、季节性情感障碍及其组合。
3.权利要求1的方法,其中所述组合物被定期施用至少1年。
4.权利要求3的方法,其中所述组合物被每日施用。
5.权利要求1的方法,其中所述组合物选自药剂、食物产品和食物产品补充剂。
6.预防抑郁的方法,其包括给处于抑郁风险中的个体施用治疗有效量的选自薄荷醇、冰素及其组合的化合物。
7.权利要求6的方法,其中所述抑郁选自单相抑郁、双相抑郁、急性抑郁、慢性抑郁、亚慢性抑郁、精神抑郁症、产后抑郁、更年期抑郁症状、季节性情感障碍及其组合。
8.权利要求6的方法,其中所述组合物被定期施用至少1年。
9.权利要求8的方法,其中所述组合物被每日施用。
10.权利要求6的方法,其中所述组合物选自药剂、食物产品和食物产品补充剂。
11.用于治疗或预防抑郁的组合物,其包含治疗有效量的选自薄荷醇、冰素及其组合的化合物。
12.权利要求11的组合物,其中所述组合物是药剂。
13.权利要求11的组合物,其中所述组合物是食物产品。
14.权利要求13的组合物,其中所述食物产品包含选自蛋白质、碳水化合物、脂肪及其组合的组分。
15.权利要求11的组合物,其中所述组合物是食物产品补充剂。
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- 2014-05-23 US US14/892,016 patent/US20160108005A1/en not_active Abandoned
- 2014-05-23 AU AU2014270339A patent/AU2014270339A1/en not_active Abandoned
- 2014-05-23 EP EP14726946.8A patent/EP3003294A1/en not_active Withdrawn
- 2014-05-23 JP JP2016514430A patent/JP2016524609A/ja not_active Withdrawn
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US7897781B2 (en) * | 2006-05-10 | 2011-03-01 | Janssen Pharmaceutica Nv | Cold menthol receptor-1 antagonists |
US20120190674A1 (en) * | 2007-07-18 | 2012-07-26 | Branum Shawn T | Sulfonamides as trpm8 modulators |
US20100292276A1 (en) * | 2009-05-15 | 2010-11-18 | Calvo Raul R | Benzimidazole derivatives useful as trp m8 receptor modulators |
CN102725401A (zh) * | 2009-07-10 | 2012-10-10 | 哈佛大学校长及研究员协会 | 作为抗炎药的永久带电荷的钠和钙通道阻断剂 |
CN102258751A (zh) * | 2011-07-21 | 2011-11-30 | 泰一和浦(北京)中医药研究院有限公司 | 用于治疗忧郁症、消愁解忧、善解抑郁的中药薄荷 |
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US20160108005A1 (en) | 2016-04-21 |
WO2014187943A1 (en) | 2014-11-27 |
EP3003294A1 (en) | 2016-04-13 |
AU2014270339A1 (en) | 2015-10-08 |
JP2016524609A (ja) | 2016-08-18 |
BR112015028884A2 (pt) | 2017-07-25 |
CA2908378A1 (en) | 2014-11-27 |
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