CN103596573A - 处理高皮质醇血症、头痛失调、神经性疼痛及相关失调的方法 - Google Patents
处理高皮质醇血症、头痛失调、神经性疼痛及相关失调的方法 Download PDFInfo
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Abstract
本公开涉及使用包含积雪草苷和羟基积雪草苷可选地连同至少一种赋形剂一起的组合物治疗和处理库欣氏综合症、头痛失调和神经性疾病。所述治疗能够延伸至肌痛和其他相关疾病病症。
Description
技术领域
本公开涉及使用包含积雪草苷和羟基积雪草苷(madecasosside)可选地连同至少一种赋形剂一起的组合物治疗和处理高皮质醇血症、头痛失调和神经性疼痛。
背景技术
血清素是一种神经递质,参与多种脑功能。血清素受体,通常已知为5-羟色胺(5-HT)受体,广泛表达于体内不同位点如脑、血管、心脏瓣膜、胃肠道、血小板等。血清素结合至5-HT受体,能够诱导兴奋性神经传导和抑制性神经传导。有14种5-HT受体已被识别。血清素能够产生复杂的心血管效应,包括低血压或高血压、血管扩张或血管收缩、心动过缓或心动过速等。由血清素产生的作用取决于其结合的5-HT受体的性质以及受体的密度和敏感性。血清素受体5-HT1A、5-HT1B和5-HT1D表达于血管和中枢神经系统中。血清素结合于这些受体,会导致血管中发生血管收缩。药物结合于5-HT1B和5-HT1D受体能够用于治疗偏头痛。然而,由于5-HT1B受体也表达在心脏瓣膜,则长期给予这些药物能够导致心脏瓣膜疾病。类似地除了血管收缩之外,5-HT1A受体还参与感受伤害性信号传导。与标准阿片类药物相比较,5-HT1A受体的激动剂能够降低疼痛感知至大约80%的显著水平。因此,显然血清素的下游效应根据其结合的5-HT受体类型而变化。
头痛失调的国际分类(第二版)将偏头痛描述为神经血管失调,其特征在于严重的并且悸动的单侧头痛,伴有厌食、恶心、呕吐、畏光及/或畏声。最常见类型的偏头痛是:(i)具有以内脏症状,感觉症状或运动症状开始的先兆随后头痛的偏头痛;和(ii)无先兆-头痛的偏头痛,类似于(i)而之前没有先兆。
现有许多理论用于描述偏头痛的病因。血管理论指出,偏头痛源自由血管舒张物质如神经肽、神经激肽等的释放所致的血管扩张。普遍接受的是这种神经血管综合症主要是由于三叉神经血管系统的激活所致。可能参与偏头痛的某些脑结构已经被识别如下:脑膜中肥大细胞包围的脑膜动脉;大的脑动脉;来自脑膜动脉和脑动脉的三叉神经;和将三叉神经节连接至三叉神经核尾侧(TNC)的三叉神经。TNC将感受伤害信号传递至丘脑和皮质中高级疼痛中心。激活三叉神经还能够引起各种神经肽的释放,包括感觉神经末梢处的降钙素基因相关肽。这会引起导致神经发炎的血管病理生理学。
血清素理论实际上是一个宽泛的论述,其支持偏头痛发作期间血清素和5-HIAA的增加作用。据报道,与正常受试者相比较,偏头痛患者显示出大脑中血清素的合成增加。这可能会导致皮质过度兴奋。有趣的是,还据报道,偏头痛是一种低血清素综合症。因此,偏头痛中血清素的参与并没有定论。其他假说支持激素和解剖学中的变化在偏头痛发展中起作用的功能。因此,偏头痛的病理生理学是非常复杂的,并且理解还不是很清楚。
选择性血清素再摄取抑制剂(SSRI)是一类通常用于治疗抑郁失调和焦虑失调的化合物。它们通过抑制其再摄取进入突触前神经元和增加突触间隙中可结合至突触后受体的血清素而增加神经递质血清素的细胞外浓度。有一种误解的概念,即所有SSRI都是有用的偏头痛药物。这不是正确的,因为升高水平的血清素能够以相等亲合力结合至所有14种5-HT受体并且这些中的许多对于偏头痛是禁忌的。此外,对于许多与其他CNS病症相关联的许多5-HT受体蛋白的表达还有不确定性。例如,据报导,5-HT1A受体在CNS中在高神经甾体水平下并未合成。
Lampl等人(2010)在发表于European Neurological Journal中关于偏头痛预防的抗抑郁药的文章中严格分析了有关SSRI对偏头痛疗效的公开数据并得出结论认为SSRI的有益效果等效于在长期治疗之后在安慰剂组中所见结果。这表明,SSRI一般对于偏头痛没用。了解5-HT受体亚型的分子的选择性对于确定其参与偏头痛治疗是至关重要的。
基于偏头痛的定义及其已知的病理生理学,显然理想的抗偏头痛药物应该抑制血管扩张(或引起血管收缩)并降低疼痛感知或伤害感受。药物的这两种直接作用将提供从偏头痛相关症状的潜在缓解。5-HT1A受体成为实现这两种作用的理想靶标。选择性5-HT1A受体激动剂有可能提供比护理偏头痛的现行标准即曲普坦类药物更好的抗偏头痛疗法。
神经性疼痛是另一种病理学疼痛病症,其特征是与感觉刺激以及疼痛部位的超敏性无关的持久性神经痛。这与许多疾病相关,如糖尿病、酒精中毒、血管炎、先天性多发性神经病、脊髓损伤、癌症、中风、HIV、退行性神经疾病、格林-巴利综合症、疱疹后神经痛和三叉神经痛。神经性疼痛是由外周或中枢神经系统的病变或功能障碍所致,这会产生感觉损失、感觉异常和疼痛的症状。
神经性疼痛不是单一的综合症。这证明了各种底层机制,包括神经瘤的异位性冲动,受损神经的钠和钙通道的变化,交感神经兴奋,以及缺陷性中央抑制通路是一些病理机制。
目前,还没有治疗方法能够防止神经性疼痛的发展。患有神经性疼痛的患者对非甾体类抗炎药(NSAID)没有反应。抗抑郁药和抗惊厥剂是为了缓解疼痛开出的护理标准。然而,这些药物具有不完全的疗效和严重的副作用。治疗神经性疼痛的抗抑郁药的作用机制尚未完全了解。Saarto等人(2010)在其发表于The Cochrane Library中关于神经性疼痛的抗抑郁药的综述中指出使用抗抑郁药的患者仅约三分之一从神经性疼痛中缓解,而约五分之一的患者由于严重的副作用停止治疗。基于公开的临床试验的现有证据,SSRI药物在治疗神经性疼痛中无效,而三环类抗抑郁药在提供临床显著的疼痛缓解方面更有效。5-HT1A受体激动剂在降低疼痛感知方面的活性可能具有治疗神经性疼痛的潜力。
Meijer等人(1994,Eur J Pharmacol.,Vol.266,No.3,pp.255-61)证明大鼠海马细胞长期暴露于神经类固醇如皮质甾酮会抑制5-HT1A受体mRNA的表达。在人体中应激的情况下,过量的神经类固醇分泌能够下调5-HT1A受体表达,这进而增加疼痛敏感性。这解释了患抑郁症的患者所经历的肌痛或慢性疼痛。身体组织长期暴露于高水平皮质醇神经类固醇会导致称为库欣氏综合症或高皮质醇血症的失调。库欣氏综合症可以由长期外源性给予类固醇激素,如糖皮质激素,促肾上腺皮质激素(ACTH),含雌激素的避孕丸和体内其他内源性异常所诱发。库欣氏综合症的症状包括以下的一种或多种:糖尿病、高血压、上身肥胖、脖子周围脂肪沉积增加、脸圆、胳膊和腿变瘦、严重疲劳、肌肉无力等。易怒、焦虑、认知障碍和抑郁是与库欣氏综合症有关的常见行为症状。库欣氏综合症的治疗包括给予抑制皮质醇药物如酮康唑和甲吡酮连同用于症治疗的药物一起。
本公开涉及治疗和处理库欣氏综合症、偏头痛、神经性疼痛、肌痛和相关疼痛。这些是需要长期处理治疗的神经失调。本公开旨在使用植物来源的包含15-50%积雪草苷和20-50%羟基积雪草苷可选地连同赋形剂一起的组合物,作为长期给予患有这些疾病的患者的安全且有效的治疗选择。
Bhaskaran等人(US20080194499)公开了包含15%至50%积雪草苷和20-50%羟基积雪草苷用于血清素再摄取抑制的组合物。该文献指出,这种组合物有助于治疗由血清素水平降低介导的疾病,即抑郁症,情绪升高,胃排空等(通过增加血清素神经递质的水平)。该文献教导了这种组合物能够通过阻断血清素再摄取来增强血清素疗效。然而,并没有建议和明确使用这种组合物来解决感受伤害和神经性疼痛知觉、缓解血管舒张和调节神经性类固醇过度分泌的作用。该申请也没有教导关于减少与库欣氏综合症(高皮质醇血症)相关症状的任何东西。该申请谈论了通过降低突触前受体的再摄取来升高血清素浓度。
发明内容
因此,本公开涉及处理选自包括高皮质醇血症,头痛失调和神经性疼痛或它们的病症的任何组合的组中的疾病病症的方法,所述方法包括向需要其的受试者给予药学有效量的包含积雪草苷和羟基积雪草苷可选地连同至少一种赋形剂一起的组合物的操作。
具体实施方式
本公开涉及处理选自包括高皮质醇血症、头痛失调和神经性疼痛或它们的病症的任何组合的组中的疾病病症的方法,所述方法包括向其需要其的受试者给予药学有效量的包含积雪草苷和羟基积雪草苷、可选地连同至少一种赋形剂一起的组合物的操作。
在本公开的一个实施方式中,积雪草苷浓度为约15%至约50%,而羟基积雪草苷浓度为约20%至约50%。
在本公开的另一个实施方式中,所述组合物获自植物积雪草(CentellaAsiatica)。
在本公开的又另一个实施方式中,所述高皮质醇血症的病症是库欣氏综合症。
在本公开的另一个实施方式中,所述头痛失调的病症选自包括偏头痛,紧张性头痛和丛集性头痛或它们的任何组合的组中。
在本公开的另一个实施方式中,所述组合物以每天约1mg/kg至约100mg/kg体重的剂量给药。
在本公开的另一个实施方式中,所述受试者是动物或人。
在本公开的另一个实施方式中,所述赋形剂选自包括成粒剂、粘合剂、润滑剂、崩解剂、增甜剂、助流剂、抗粘剂、防静电剂、表面活性剂、抗氧化剂、树胶、包衣剂、着色剂、调味剂、包衣剂、增塑剂、防腐剂、悬浮剂、乳化剂、植物纤维素物质和滚圆剂或它们的任何组合的组中。
在本公开的另一个实施方式中,所述组合物配制成选自包括片剂、糖锭剂、锭剂、水性或油性悬浮液、软膏、贴剂、凝胶、洗剂、牙粉、胶囊剂、乳液、乳膏、喷雾剂、滴剂、可分散性粉末或颗粒、处于硬或软凝胶胶囊中的乳液、糖浆、酏剂、植物性药物、营养品和食品或它们的任何组合的组中的剂型。
在本公开的另一个实施方式中,所述组合物介导伤害感受、血管收缩和神经类固醇分泌的调节。
在本公开的另一个实施方式中,所述组合物选择性地结合至5-HT1A受体。
在本公开的另一个实施方式中,所述组合物以每天在动物体内1-100mg/kg以及在人体内1-50mg/kg的剂量范围给药。
在本公开的另一个实施方式中,制备包含积雪草苷和羟基积雪草苷的组合物的方法包括以下步骤:
a.从植物积雪草中获取提取物;
b.过滤和浓缩所述提取物;
c.将浓缩提取物溶解于溶剂中以获得溶液;
d.用溶剂处理所述溶液以去除脂肪物质;
e.叶绿素和其他着色剂;
f.将处理的溶液通过吸附剂以获得清澈溶液;和
d.浓缩所述清澈溶液以获得所述组合物。
在本公开的另一个实施方式中,所述溶剂选自包括杂环芳族化合物、脂族化合物、酮、醇、腈、酯、醚和它们的一种或多种的混合物的组中。
在本公开的另一个实施方式中,用于提取的溶剂优选是脂肪醇。
在本公开的另一个实施方式中,所述提取在20至38℃优选30℃的温度下实施。
在本公开的另一个实施方式中,所述提取进行6h至10h优选8h。
在本公开的另一个实施方式中,所述浓缩在40至50℃优选45℃的温度下实施。
在本公开的另一个实施方式中,所述溶剂优选去离子水。
在本公开的另一个实施方式中,所述溶剂选自包括己烷、石油醚和甲基异丁基酮的组中。
在本公开的另一个实施方式中,所述吸附剂选自包括树脂、木炭、硅胶及它们的混合物的组中。
在本公开的另一个实施方式中,所述浓缩在50至65℃的温度下实施。
本公开还涉及生产包含积雪草苷和羟基积雪草苷,可选地连同赋形剂一起而用于库欣氏综合症、偏头痛、神经性疼痛和肌痛的药物。
在本公开的另一个实施方式中,所述赋形剂选自包括成粒剂、粘合剂、润滑剂、崩解剂、增甜剂、助流剂、抗粘剂、防静电剂、表面活性剂、抗氧化剂、树胶、包衣剂、着色剂、调味剂、包衣剂、增塑剂、防腐剂、悬浮剂、乳化剂、滚圆剂和植物衍生的纤维素材料的组中。
在本公开的另一个实施方式中,所述组合物配制成型选自包括片剂、糖锭剂、锭剂、水性或油性悬浮液、软膏、贴剂、凝胶、洗剂、牙粉、胶囊剂、乳液、乳膏、喷雾剂、滴剂、可分散性粉末或颗粒、处于硬或软凝胶胶囊中的乳液、糖浆、酏剂、搽剂、软膏、皮肤贴剂、喷鼻剂、植物性药物、营养品和食品的组中的各种剂型。
在本公开的另一个实施方式中,暗示了所述组合物可以包含较小比例的来自积雪草种子的纤维素材料。
在以下实施例的帮助下将进一步详细阐述本公开。然而,这些实施例不应该解释为限制本公开的范围。
实施例1
以干净且干燥的形式取出1kg主要包含植物积雪草的叶子和茎的地上部分,并粉碎成一定尺寸以确保100%通过20筛目尺寸的锤式粉碎机。这种材料用5L甲醇在固定床逆流提取器中在30℃下反复提取10h。在10h之后所述提取物过滤清除所有悬浮物。所述澄清的滤液在旋转蒸发器中在40下真空浓缩成半固体。向浓缩的团块中加入3L去离子水从而获得均质液体。所述液体通过将其用2L己烷冲洗两次而进行萃取,并且分出底部水层。再次将水层用1L甲基异丁基酮萃取两次。分离出底部水层,并通过吸附剂床树脂Amberlite XAD1180(400mL)床,保持流速为25mL/min并针对缺少积雪草皂苷(centella saponin)检测流出液。
所述柱子用5L过量去矿物质水彻底洗涤直至冲洗液无色。所述吸附剂柱用乙醇自由洗脱直到监测TLC测试显示洗脱液中无积雪草皂苷(centello saponin)。得到的洗脱液通过包含100g活性碳和250g尺寸为60至120网目的硅胶的柱子。收集得到的洗脱液,并用乙醇彻底冲洗所述柱子,并且将所有冲洗物与所述洗脱液合并并且在真空蒸馏设备中在45至50下浓缩以获得粉末。将所述粉末溶于300mL去矿物质水以获得固体含量为20%的清澈溶液,并在以下条件下在并流间接热空气喷雾干燥器中喷雾干燥:进口温度:140℃,以及出口温度:80℃。通过HPLC方法获得产率为30gm的淡黄色水溶性粉末,组成为41%积雪草苷和36%羟基积雪草苷。
实施例2:
以干净并且干燥的形式取出1kg主要包含植物积雪草的叶子和茎的地上部分,并粉碎成一定尺寸以确保100%通过20筛目尺寸的锤式粉碎机。这种材料用5L甲醇在固定床逆流提取器中在30℃下反复提取8h。在8h之后所述提取物过滤清除所有悬浮物。所述澄清的滤液在旋转蒸发器中40下真空浓缩成半固体。向浓缩的团块中加入3L去离子水以获得均质液体。所述液体通过将其用2L己烷冲洗两次来进行萃取,并且分离出底部水层。再次将水层用1L甲基异丁基酮萃取两次。分离出底部水层,并通过吸附剂树脂床Amberlite XAD1180(400mL)床,保持流速为25mL/min并针对缺少积雪草皂苷监测所述流出液。
所述柱子用5L过量去矿物质水彻底洗涤直至冲洗液无色。所述吸附剂柱用异丙醇洗脱直到监测TLC测试显示洗脱液中无积雪草皂苷。得到的洗脱液通过包含100g活性碳和250g尺寸为60至120网目的硅胶的柱子。收集得到的洗脱液,并用异丙醇彻底冲洗所述柱子,并且所有冲洗物与所述洗脱液合并并且在真空蒸馏设备中在45至50下浓缩以获得粉末。将所述粉末溶于300mL去矿物质水中以获得固体含量为20%的清澈溶液,并在以下条件下在并流间接热空气喷雾干燥器中喷雾干燥:进口温度:140℃,以及出口温度:80℃。通过HPLC方法获得产率为32gm的淡黄色水溶性粉末,组成为39%积雪草苷和34%羟基积雪草苷。
实施例3:
将10g来自实施例1的41%积雪草苷和36%羟基积雪草苷与1g99%纯的积雪草苷混合从而获得包含11g46.3%积雪草苷和32.7%羟基积雪草苷的组合物。这个实施例展示了通过混合具有不同浓度的积雪草苷和羟基积雪草苷的不同组合物获得包含15%至50%积雪草苷和20%至15%羟基积雪草苷的希望的组成范围的方法。本领域技术人员应当理解到,本文中获得的组合物可以通过混合通过从植物来源提取或通过所述组分的化学合成获得的组分(积雪草苷和羟基积雪草苷)而获得。
在以下实施例中针对生理活性进一步测试包含15%至50%积雪草苷和20%至50%羟基积雪草苷的测试组合物:
实施例4:测试组合物在嗅球切除大鼠中的活性
双侧嗅球切除术(OBX)是慢性抑郁症的动物模型,其证实看下丘脑-垂体-肾上腺(HPA)轴在维持动态平衡中的关键作用。OBX对HPA轴产生干扰并带来标志动物慢性抑郁症的行为和生理变化。在手术恢复后,OBX动物显示出体重急剧增加。这种体重增加伴随其他特征性生理变化,如食物摄入量增加、抑郁发作、钠浓度和皮质甾酮水平升高。这些症状据发现与库欣氏综合症有关。有趣的是注意到OBX模型模拟了库欣氏综合症的病症。
库欣氏综合症与体重过重、胰岛素抵抗性、抑郁、食物摄入量增加、皮质醇分泌增加的病症有关。为了研究包含39%积雪草苷和34%羟基积雪草苷的测试组合物的活性,我们使用了双侧嗅球切除(OBX)大鼠的动物模型,其产生在库欣氏综合症中所见的所有上述症状。
步骤:雄性Wistar大鼠采用氯胺酮(80mg/kg)麻醉,并通过附连至水泵的钝头皮下注射针头以手术方式吸出嗅球,而不破坏额叶。允许这些动物从手术中恢复持续2周的时间。用测试组合物进行长期治疗持续14天。通过将动物放置于开放场地中并观察行走活动得分,后肢站立得分和理毛行为得分持续5min的时间来进行行为测试。走动行为得分作为每3min穿过方格的平均数进行测定。后肢站立得分作为每3min后肢站立活动的数量进行测定。理毛行为得分作为每3min理毛活动的数量进行测定。在治疗的最后一天,抽血测定血清皮质甾酮。皮质甾酮是在啮齿类动物中发现的主要糖皮质激素,并且它是人体中发现的皮质醇激素的等效物。
结果:OBX动物证明与假对照组中所见的7.9%正常体重增加相比较,体重增长21.28%。所述测试组合物在3、10和30mg/kg的剂量下显著抑制OBX诱发的体重增加达12%、16.88%和18.56%。
表1:测试组合物对嗅球切除大鼠体重的影响(以克计)
n=5;数据表示为平均值±SEM;数据通过双向ANOVA接着进行邦费罗尼后检验(Bonferroni Post test)进行分析;###P<0.001与假对照组相比较;***P<0.001,**P<0.01和*P<0.05与OBX对照组相比较。
在手术恢复的14天后监测所有试验动物的食物摄入量。与假对照组相比较,在OBX对照组中的动物表现出36%的食物摄入量增加。在10和30mg/kg下用测试组合物治疗14天,显著地正常化食物摄入量。
表2:测试组合物对嗅球切除大鼠食物摄取量的影响(以克/天计)
n=5;数据表示为平均值±SEM;数据通过双向ANOVA接着进行邦费罗尼后检验(Bonferroni Posttest)进行分析;###P<0.001与假对照组相比较;***P<0.001与OBX对照组相比较。
进行开放场地测试以评价这些动物的运动行为。OBX动物表现出活动过度,证实了抑郁症。行走活动得分增加标志着暴露于新环境的抑郁动物的焦虑。在3、10和30mg/kg剂量下测试组合物显著降低了这种活动过度达30.3%、51.2%和64.7%。
表3:在开放场地测试中通过运动行为测定的测试组合物对抗OBX诱发抑郁的影响
n=5;数据表示为平均值±SEM;数据通过双向ANOVA接着进行邦费罗尼后检验(Bonferroni Posttest)进行分析;###P<0.001和##P<0.01与假对照组相比较;***P<0.001和*P<0.05与OBX对照组相比较。
OBX对照动物表现出血液中皮质甾酮过度分泌。在所有剂量下用测试组合物治疗的动物显著地降低了血液中皮质甾酮的水平。OBX诱发血清钠浓度增加,其在10和30mg/kg下被测试组合物显著降低。还观察到血糖水平的降低。
表1:在嗅球切除大鼠中测试组合物对血清钠和皮质甾酮浓度的影响
n=5;数据表示为平均值±SEM;数据通过对每个参数单向ANOVA接着进行杜尼特多重比较检验(Dunnett Multiple Comparison test)进行分析;###P<0.001与假对照组相比较;***P<0.001和*P<0.05与OBX对照组相比较。
该研究显示测试组合物在治疗由嗅球切除大鼠证实的内源性因素诱发的库欣氏综合症病症(即体重增加、抑郁、食量增加、皮质醇分泌过多和血清钠增加)中的疗效。因此,所述测试组合物在治疗和处理库欣氏综合症和皮质醇血症的所有其他病症中是有效的。
患有抑郁症的患者经历了严重的肌肉疼痛或肌痛。这可能是由于皮质醇分泌增加所致,这进而影响疼痛调节5-HT1A受体的表达。通过降低OBX大鼠中皮质甾酮水平,所述测试组合物证实在增加疼痛耐受性方面以及因此在治疗和处理肌痛和其他神经疼痛病症中的疗效方面具有潜在用途。
实施例5:与5-HT1A受体拮抗剂组合的作用
所述测试组合物的活性通过首先用拮抗剂阻断5-HT1A受体接着用测试组合物治疗来进行评价。所述活性根据进行强迫游泳测试的测试动物的不动时间来测定。
步骤:体重25至30g雄性瑞士小白鼠(Swiss albino mice)在1mg/kg(p.o.)下用5-HT1A受体拮抗剂(NAN-190)然后在10mg/kg(p.o.)或30mg/kg(p.o.)下给予测试组合物进行治疗。治疗后1h,使所述动物进行强迫游泳试验并且测定不动时间。所用的截止时间为360s。
结果:仅使用测试组合物治疗的动物进行强迫游泳测试并且与正常对照动物相比较观察到不动时间显著减少。用10mg/kg测试组合物治疗的动物中不动时间减少约24.87%,而用30mg/kg测试组合物治疗的动物中观察到不动时间减少30.14%。通过拮抗剂阻断5-HT1A受体消除了所述测试组合物的这种活性,表明所述测试组合物的作用是通过5-HT1A受体介导的。
表2:测试组合物在强迫游泳测试中的活性
n=6;数据表示为平均值±SEM;数据通过单向ANOVA接着进行杜尼特多重比较检验进行分析。###P<0.001与正常对照组相比较。
实施例6:测试组合物在大鼠中硝化甘油诱导的痛觉过敏中的作用
这个实施例评价了通过提高疼痛耐受性所述测试组合物的潜在抗偏头痛活性。硝化甘油通过类似于人体内的偏头痛,血管舒张脑动脉而诱导大鼠中痛觉过敏。
步骤:任何性别体重200至250g的维斯塔尔(Wistar)大鼠在测试前安置于塑料笼中至少10天。使用甩尾测试仪(tail flick apparatus)(UGOBASILE)评估痛觉过敏。以这种方式将大鼠置于甩尾装置中,即尾巴遮挡光电池上的狭缝。通过IR辐射加热,并且调节光强度以获得8至12秒的正常反应。使用20秒截止时间,以防止组织损伤。当大鼠感到疼痛并且挥动其尾巴时,光落在光电池上并记录下时间。在取得基础读数后,大鼠以10mg/kg的剂量腹腔内注射硝化甘油。15min后,口服给予包含41%积雪草苷和36%羟基积雪草苷(30mg/kg)或喷他佐辛(20mg/kg)的测试组合物。在治疗后30、60、90、120、180和240min时,测定反应延迟时间。
表3:在大鼠中硝化甘油诱发的痛觉过敏中甩尾实验中的反应延迟时间
n=6;数据代表平均值±SEM;数据通过双向ANOVA接着进行邦费朗尼后检验进行分析。###P<0.001与正常对照组相比较;***P<0.001与硝化甘油对照组相比较。
结果:所述测试组合物显著逆转由动物中给予硝化甘油所诱发的疼痛敏感性增加。通过所述测试组合物引发的活性迅速起效。另外,测试组合物组中的反应延迟时间比麻醉药品喷他佐辛治疗组更接近于正常动物,这表明从疼痛中缓解而没有任何镇静副作用。这项研究证实,所述测试组合物适用于疼痛处理和治疗偏头痛,丛集性头痛,紧张性头痛和所有相关的头痛。
实施例7:测试组合物在患有偏头痛的患者中的作用
用于评价所述测试组合物抗偏头痛侵袭发生率的疗效的有前途的研究在5名确诊患有慢性偏头痛的受试者中进行评价。这些受试者以300mg剂量每日两次给予测试组合物胶囊持续1个月,并且基于研究期间的开始和结束时得到的患者报告结果来分析所述测试组合物的疗效。
表4:测试组合物在偏头痛治疗中的作用
在开始给予所述测试组合物之后,受试者报告偏头痛发作频率和强度降低。这些受试者还报告对止痛药的依赖性降低。进一步观察到,偏头痛相关的症状减少,如烦躁不安,对光、气味、噪音耐受性降低;恶心、呕吐等。因此,所述测试组合物据发现适用于预防和/或减轻人受试者中的偏头痛。
实施例8:测试组合物的配制
通过与1.5%w/w的微结晶纤维素、1%w/w的预凝胶化淀粉崩解剂、0.5%w/w的交联聚维酮和0.5%w/w硬脂酸镁抗粘附剂共混通过将包含41%积雪草苷和36%羟基积雪草苷的组合物造粒来制备实施例7中的胶囊。所述混合颗粒物填充于胶囊中。
范围为15%至50%积雪草苷和20%至50%羟基积雪草苷的所述测试组合物的类似制剂能够通过加入选自包含以下各项的列表的赋形剂而制成:成粒剂、粘合剂、润滑剂、崩解剂、增甜剂、着色剂、调味剂、包衣剂、增塑剂、防腐剂、悬浮剂、乳化剂、滚圆剂和它们的任何组合。而制剂类型可以选自由片剂、胶囊、糖锭、锭剂、粉末、糖浆剂、溶液、气溶胶、悬浮液、可分散粉末或颗粒、处于硬或软凝胶胶囊中的乳液、糖浆、酏剂、搽剂、软膏、皮肤贴剂、植物性药物、营养品和食品组成的组中。根据给药途径,可以使用不同的赋形剂/载体。本领域技术人员能够选择所述测试组合物合适的制剂用于治疗和处理高皮质醇血症(库欣氏综合症)、偏头痛、神经性疼痛、肌痛和相关的疼痛。
实施例9:测试组合物对动物中神经性疼痛的作用
使用大鼠中神经性疼痛的坐骨神经挤压损伤(SNCI)模型来评价测试组合物在治疗神经性疼痛中的治疗潜力。在SNCI模型中产生部分去神经化,这允许进行由刺激后爪神经目标引发的疼痛行为的分析。
步骤:重量220至250g的雄性维斯塔尔(Wistar)大鼠使用氯胺酮(80mg/kg)麻醉,并在无菌条件下将右侧坐骨神经暴露于高股水平下。从周围结缔组织中并且使用虹膜镊子将神经背部释放出来,并且通过将神经外膜夹在其背侧将神经固定在其位置上。使用钝头镊子挤压神经两次持续30s的时间,二者之间间隔60s。动物允许从手术中恢复过来。在手术之后的第2天,将包含41%积雪草苷和36%羟基积雪草苷的组合物以10、30和100mg/kg(p.o.)给药,并持续长达30天。对以下参数进行了评价:
a)兰德尔-瑟里拓(Randall Selitto)测试–向右后爪施加逐渐增加的机械压力并且将大鼠缩回爪时的压力记录为感受伤害阈值压力。
表5:兰德尔-瑟里拓(Randall Selitto)测试中爪缩回压力(g)
n=6;数据代表平均值±SEM;数据通过双向ANOVA接着进行邦费朗尼后检验进行分析。ns—与正常对照组相比较并不显著;###P<0.001与假对照组相比较;***P<0.001,**P<0.01和*P<0.05与SNCI对照组相比较。
b)通过使用直径为1mm刚性尼龙丝向右后爪中跖表面施力来评价冯弗雷细丝-机械触觉异常疼痛(Von Frey filament-Mechano-tactileallodynia)。右后肢快速缩回被认为是正反应,并记录下大鼠缩回其爪时的力。
表6:在冯弗雷细丝测试中爪缩回的力(克)
n=6;数据代表平均值±SEM;数据通过双向ANOVA接着进行邦费朗尼后检验进行分析。ns—与正常对照组相比较并不显著;###P<0.001与假对照组相比较;**P<0.01和*P<0.05与SNCI对照组相比较。
c)尾部浸渍测试-通过将大鼠尾巴末端部分浸渍于范围0-4℃的寒冷温度下并测定尾巴缩回反射的持续时间来评估脊髓热敏感性。使用15秒的截止时间。
表10:尾巴浸渍测试中的反应延迟时间(秒)
n=6;数据代表平均值±SEM;数据通过双向ANOVA接着进行邦费朗尼后检验进行分析。ns—与正常对照组相比较并不显著;###P<0.001与假对照组相比较;***P<0.001与SNCI对照组相比较。
d)运动协调性测试–使用转棒装置来评价运动协调性。将大鼠置于旋转棒上1分钟。从滚筒上掉落下来所花费的时间记录为握力强度。
表11:运动协调性测试中的握力强度(秒)
n=6;数据代表平均值±SEM;数据通过双向ANOVA接着进行邦费朗尼后检验进行分析。ns—与正常对照组相比较并不显著;###P<0.001与假对照组相比较;***P<0.001,**P<0.01和*P<0.05与SNCI对照组相比较。
结果:所述测试组合物显著降低大鼠中坐骨神经挤压损伤所诱发的神经性疼痛症状。在采用测试组合物慢性治疗方面观察到伤肢痛觉过敏、异常性疼痛和热敏感性的显著降低。如从转棒测试中可见,还通过所述测试组合物标准化了受伤动物的运动协调性。因此,当长期使用时所述测试组合物适用于治疗神经性疼痛及其症状。
实施例10:测试组合物在患有神经性疼痛的患者中的作用
用于评价所述测试组合物在处理神经性疼痛中的疗效的有前途的研究在患有糖尿病3至5年的50岁以上的3名患者中进行评价。这些患者被给予如实施例8中配制的测试组合物胶囊,剂量为每天300mg两次持续2个月的时间,并且基于研究期间开始和结束时得到的患者报告结果来分析所述测试组合物的疗效。
表12:测试组合物在神经性疼痛治疗中的作用
在开始给予所述测试组合物之后,所述受试者报告突发性疼痛发作的频率降低。报告了由触发因素如触摸,冷/热水浴,曝光等引起的烧灼感、麻刺感、麻木和疼痛的强度降低。所述测试组合物据发现适用于处理人受试者中的神经性疼痛。
实施例11:测试组合物的喷鼻制剂
将55mg包含46.8%积雪草苷和31.8%羟基积雪草苷的测试组合物溶解于140mL生理盐水(0.09%w/v NaCl)中。向此溶液中加入10mg苯扎氯铵,并搅拌1h。将该混合物灭菌,通过0.4μm过滤器过滤,并填充于鼻喷雾剂瓶中。喷鼻剂的一次喷射递送140μL制剂,这相当于55μg所述测试组合物。
实施例12:鼻喷剂在大鼠中硝化甘油诱发的痛觉过敏中的作用
该实施例评价了配制成鼻喷剂的所述测试组合物的潜在活性。硝化甘油通过类似于人体中偏头痛的脑动脉血管舒张诱发大鼠中的痛觉过敏。
步骤:在测试前将任意性别体重200至250g的维斯塔尔(Wistar)大鼠安置于塑料笼中至少10天。使用甩尾测试仪(tail flick apparatus)(UGO BASILE)评估痛觉过敏。以这种方式将大鼠置于甩尾装置中,即尾巴遮挡光电池上的狭缝。通过IR辐射加热,并且调节光强度以获得8至12秒的正常反应。使用20秒截止时间,以防止组织损伤。当大鼠感到疼痛并且摆动其尾巴时,光落在光电池上并记录下时间。在取得基础读数后,大鼠以10mg/kg的剂量腹腔内注射硝化甘油。15min后,将实施例11中配制的测试组合物喷到鼻腔中。在治疗后30、60、90、120、180和240min时,测定反应延迟时间。
表13:测试组合物的鼻喷剂在大鼠中硝化甘油诱发的痛觉过敏中的作用
n=6;数据代表平均值±SEM;数据通过双向ANOVA接着进行邦费朗尼后检验进行分析。###P<0.001与正常对照组相比较;***P<0.001与硝化甘油对照组相比较。
结果:所述配制成鼻喷剂的测试组合物显著逆转由硝化甘油诱发的疼痛敏感性。活性的发作直接类似于实施例6中所示的口服治疗。使用鼻喷剂达到这种疗效所需的剂量也显著较低的,这证实通过鼻部途径增强了所述测试组合物的递送。这项研究证实,配制成鼻喷剂的测试组合物在疼痛处理中是安全和有效的。因此,配制成鼻喷剂的测试组合物适用于治疗和处理高皮质醇血症(库欣氏综合症)、偏头痛、神经性疼痛、肌痛和相关疼痛。
实施例13:测试组合物的环糊精络合
该实施例表明,所述测试组合物能够与环糊精即α、β和γ-环糊精络合以增强所述测试组合物对胃液或肠液的稳定性。
取200mL去矿物质水并在搅拌下于80至85℃下向其中加入50gβ-环糊精以获得澄清溶液。在85℃下在搅拌下在1h的时间内分成多个部分向其中缓慢加入40g含46.8%积雪草苷和31.8%羟基积雪草苷的测试组合物。通过形成澄清溶液,所述混合物完全溶解是至关重要的,在此之后所述溶液在搅拌下保持于85至90℃下持续3h。3h之后,溶液在室温下缓慢冷却,并将溶液在搅拌下保持另外8h。溶液过滤,并在75℃下真空干燥至恒重。产量为73g。100mg这种络合物溶解于7mL去矿物质水中。
Claims (9)
1.一种处理选自包括高皮质醇血症、头痛失调和神经性疼痛或它们的病症的任何组合的组中的疾病病症的方法,所述方法包括向需要其的受试者给予药学上有效量的包含积雪草苷和羟基积雪草苷、可选地连同至少一种赋形剂一起的组合物的操作。
2.根据权利要求1所述的方法,其中所述积雪草苷的浓度为约15%至约50%,而羟基积雪草苷的浓度为约20%至约50%。
3.根据权利要求1所述的方法,其中所述组合物获自植物积雪草。
4.根据权利要求1所述的方法,其中所述高皮质醇血症的病症是库欣氏综合症。
5.根据权利要求1所述的方法,其中所述头痛失调的病症选自包括偏头痛、紧张性头痛和丛集性头痛或它们的任何组合的组中。
6.根据权利要求1所述的方法,其中所述组合物以每天约1mg/kg至约100mg/kg体重范围的剂量给予。
7.根据权利要求1所述的方法,其中所述受试者是动物或人。
8.根据权利要求1所述的方法,其中所述赋形剂选自包括成粒剂、粘合剂、润滑剂、崩解剂、增甜剂、助流剂、抗粘剂、防静电剂、表面活性剂、抗氧化剂、树胶、包衣剂、着色剂、调味剂、包衣剂、增塑剂、防腐剂、悬浮剂、乳化剂、植物纤维素物质和滚圆剂或它们的任何组合的组中。
9.根据权利要求1所述的方法、其中所述组合物配制成选自包括片剂、糖锭剂、锭剂、水性或油性悬浮液、软膏、贴剂、凝胶、洗剂、牙粉、胶囊剂、乳液、乳膏、喷雾剂、滴剂、可分散性粉末或颗粒、处于硬或软凝胶胶囊中的乳液、糖浆、酏剂、植物性药物、营养品和食品或它们的任何组合的组中的剂型。
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