CN109641030B - 用于调节阿片类戒断症状的方法和组合物 - Google Patents
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Abstract
一种筛选用于调节哺乳动物阿片类戒断症状的化合物或组合物的方法。该方法包括以下步骤:选择一组试验动物;将该组分成两个小组;在两个小组中均诱导泛连接蛋白‑1活化或表达;将候选化合物给药至第一小组;将安慰剂给药至第二小组;测量在两个小组的试验动物的脊髓小胶质细胞中释放的ATP的量;对第一小组试验动物和第二小组试验动物的脊髓小胶质细胞中释放的ATP的量的差异进行定量;如果在第一小组中释放的ATP的量和第二小组中释放的ATP的量的差异大于25%,则将该候选化合物配制到药物组合物中。还公开了用于调节受试者的阿片类戒断症状的包含泛连接蛋白‑1抑制剂的药物组合物。所述抑制剂可以是具有氨基酸序列WRQAAFVDSY的10panx肽、甲氟喹或丙磺舒。
Description
技术领域
本公开一般地涉及与阿片类或阿片类样药物有关的物质使用紊乱的治疗。更特别地,本公开涉及筛选化合物和组合物的方法,该方法用于鉴定和选择有效调节阿片类戒断症状的候选治疗化合物和组合物。
背景技术
鸦片制剂是用于治疗疼痛最有效和最广泛的处方药物之一。然而,终止鸦片制剂治疗疼痛疗法的一个主要问题是可能困扰慢性鸦片制剂使用者的令人衰弱的戒断综合征。对于鸦片制剂戒断所涉及的机制知之甚少,而且可用于治疗戒断的有限的临床策略没有效果。
发明内容
本公开的实施方案一般地涉及泛连接蛋白-1(Panx1)通道作为治疗吗啡戒断的新治疗靶标的应用。我们发现吗啡治疗诱导脊髓椎板I/II神经元的突触可塑性,这表现为纳洛酮催促吗啡戒断后的长期突触促进。这种突触促进通过激活在小胶质细胞上表达的Panx1通道而被严格控制。药理学上阻断Panx1,或特别地从小胶质细胞中遗传性地消融该通道,阻断脊髓的突触促进并减轻吗啡戒断的行为后遗症。还测试了临床上应用的Panx1的非选择性抑制剂,甲氟喹和丙磺舒。这些化合物在小鼠和大鼠中有效地阻断了小胶质细胞中Panx1的活化,并改善了吗啡戒断的严重程度。本申请中公开的发现揭示了小胶质细胞通过Panx1发出信号以产生吗啡戒断症状的细胞的和行为的推论的新机制。因此,靶向Panx1提供了用于治疗鸦片制剂戒断症状的一种潜在的新治疗方法。
附图说明
将参考以下附图来一起描述本公开的内容,其中:
图1是描述用于本申请公开的使用大鼠和小鼠作研究的吗啡和药物给药范例的示意图。
图2是显示吗啡和对照处理大鼠的累积戒断评分和免疫毒素Mac-1-皂草素对戒断行为的影响的图表,其中“CTR”表示对照处理,“MS”表示用硫酸吗啡的处理,“MS Mac-1”表示鞘内注射Mac-皂草素的处理,“MS Sap”表示鞘内单独注射皂草素的处理;
图3是显示鞘内注射盐水、皂草素或Mac-1-皂草素对对照动物(盐水处理的)动物和吗啡处理动物的体细胞和自主神经细胞的戒断行为的影响的一系列图表。
图4是一系列显微照片图,显示在吗啡或盐水处理后5天,以及在小胶质细胞耗尽免疫毒素Mac1-皂草素或未缀合的皂草素(标尺代表50μm)后5天,在大鼠脊髓背角中的CD11b表达;
图5是显示对照大鼠和吗啡处理的小鼠中Mac1-皂草素或未缀合的皂草素对CD11b免疫反应性的影响的图表。
图6是显示在吗啡或对照注射后,或脊髓小胶质细胞耗尽Mac-1-皂草素后,用热甩尾试验评估的吗啡镇痛作用的图表。
图7显示了蛋白质印迹和直方图,比较了吗啡戒断的大鼠与对照大鼠在腰髓的局部Panx1蛋白的表达。
图8是显示使用荧光激活细胞分选的CD11b阳性和CD11b阴性群体中Panx1的表达的直方图。
图9是显示使用荧光激活细胞分选的CD11b阳性(MS)和CD11b阴性群体(CTR)中Panx1染色的平均荧光强度(MFI)的图表。
图10显示了吗啡或盐水(对照)处理5天后的原代小胶质细胞培养物中总Panx1蛋白的蛋白质印迹和直方图。
图11显示了吗啡或盐水(对照)处理5天后的永生化BV-2小胶质细胞培养物中总Panx1蛋白的蛋白质印迹和直方图。
图12显示用BzATP(150μM)刺激30分钟后,吗啡、吗啡/纳洛酮和对照处理的BV-2小胶质细胞中的YO-PRO-1染料摄取的代表性图像和/或痕迹;
图13是显示在30分钟时,与单用吗啡处理和单用盐水处理的小胶质细胞相比,用吗啡或盐水处理的BV-2小胶质细胞中的YO-PRO-1染料摄取的代表性痕迹,以及用纳洛酮(10μM)预处理的小胶质细胞相对于吗啡处理的小胶质细胞中增强的总染料摄取的代表性痕迹的图表。
图14是显示用纳洛酮(10μM)预处理10分钟或非活性肽scrpanx(10μM)对BzATP诱发的染料摄取效果的直方图。
图15是显示在30分钟时,与盐水处理的小胶质细胞或ECS刺激的小胶质细胞相比,用Panx1阻断剂10panx(10μM)来处理经吗啡处理过的小胶质细胞的增强的总染料摄取的影响的图表。
图16是显示在30分钟时,与盐水处理的小胶质细胞或ECS刺激的小胶质细胞相比,用Panx1阻断剂10panx(10μM)预处理之后再用BzATP(150μM)刺激30分钟,对吗啡处理过的小胶质细胞的增强的总染料摄取效果的图表。
图17是显示鞘内Panx1阻断剂10panx对吗啡戒断的行为体征的影响的图表。
图18是一系列显微照片图像,显示他莫昔芬和载体处理的Cx3cr1::Panx1flx/flx小鼠脊髓背角中Cre报道分子eYFP和CD11b的表达。
图19是一系列显微照片图像,显示对照小鼠和吗啡处理小鼠的脊髓背角中Cre报道分子eYFP和CD11b的表达。
图20是显示在施用他莫昔芬或载体5天后,Ai14-tdTomato-报道分子小鼠中的共标记的eYFP和tdTomato细胞百分比的图表。
图21是从成年Cx3cr1::Panx1flx/flx小鼠中分离的eYFP阳性小胶质细胞的显微照片图像。
图22是显示从他莫昔芬或载体预处理过的成年Cx3cr1::Panx1flx/flx小鼠中分离的小胶质细胞中BzATP诱发的YO-PRO-3染料摄取的图表。
图23是显示他莫昔芬对吗啡处理的小鼠和对照小鼠中钙指示剂染料ura-2AM的摄取的影响的图表。
图24是表示对于Cx3cr1::Panx1flx/flx小鼠使用热尾部浸渍试验的吗啡诱导的镇痛作用的图表。
图25显示了吗啡处理的小鼠和对照小鼠的各自的自主神经细胞和体细胞戒断行为的图表。
图26显示了他莫昔芬对吗啡处理的和对照的Cx3cr1::Panx1flx/flx小鼠脊髓背角中CD11b表达的影响的显微照片图像。
图27是显示吗啡处理的小鼠和对照的Cx3cr1::Panx1flx/flx小鼠的脊髓背角中CD11b表达的面积百分比的图表。
图28是显示他莫昔芬和载体处理的Cx3cr1-cre::Panx1flx/flx小鼠(从小胶质细胞中靶向缺失Panx1而产生的突变小鼠,即从Cx3cr1表达细胞中由他莫昔芬诱导而缺失Panx1的小鼠)中的纳洛酮催促戒断的图表。
图29是举例说明小胶质细胞Panx1(而不是外周Cx3cr1表达细胞)直接参与吗啡戒断过程的图表。
图30是显示在吗啡施用前接受了5天他莫昔芬处理的Cx3cr1::Panx1flx/flx小鼠和Pnx1flx/flx小鼠的戒断评分的图表。
图31是显示在纳洛酮催促戒断前1小时,给吗啡依赖性的经过他莫昔芬和载体处理的Cx3cr1::Panx1flx/flx小鼠紧急鞘内注射Panx1阻断剂10panx的影响的图表。
图32显示了在吗啡或盐水处理5天后,载体和他莫昔芬处理的Cx3cr1::Panx1flx /flx小鼠的脊髓背角中cFos表达的显微照片图像。
图33是显示在吗啡或盐水处理5天后,他莫昔芬和载体处理的Cx3cr1::Panx1flx /flx小鼠的脊髓浅层椎板中cFos免疫反应神经元的分布的图表。
图34是显示在吗啡处理和对照处理的Cx3cr1::Panx1flx/flx载体小鼠的脊髓背角(SDH)中,施用纳洛酮(10μM)诱导的场突触后电位(fPSPs)促进的图表。
图35是显示吗啡处理的突变小鼠中纳洛酮不引起SDH神经元促进的图表。
图36是显示在吗啡处理的和在他莫昔芬Cx3cr1::Panx1flx/flx小鼠中SDH记录的最后5分钟期间的平均fPSP面积的图表。
图37是显示在低频(2Hz)电刺激背根神经(黑色箭头)后,他莫昔芬和载体处理的Cx3cr1::Panx1flx/flx小鼠的椎板I/II中fPSP的促进作用的图表。
图38是显示在他莫昔芬和载体处理的Cx3cr1::Panx1flx/flx小鼠中的电促进实验的最后5分钟的平均fPSP面积的图表。
图39是显示来自吗啡处理的或对照突变小鼠的腰髓切片中的ACSF超滤液(superfusate)中纳洛酮刺激的ATP水平的图表。
图40是表示在吗啡或盐水处理5天后,从纳洛酮或ECS刺激的培养的小胶质细胞中收集的上清液中ATP水平的图表。
图41是显示在吗啡依赖性的和对照突变小鼠中紧急鞘内注射ATPγS(100μM,在纳洛酮之前立即给予)的效果的图表。
图42是显示在吗啡依赖性的大鼠中鞘内注射腺苷三磷酸双磷酸酶(ATP酶,10单位,纳洛酮之前15分钟)和ARL67156(ATP酶抑制剂,10纳摩尔,纳洛酮之前15分钟)以减轻戒断症状的效果的图表。
图43是显示全身施用甲氟喹(MFQ)或丙磺舒(PRB)对吗啡处理的和对照的大鼠戒断行为的影响的图表。
图44是显示甲氟喹对BV-2小胶质细胞培养物中YO-PRO-3染料摄取的影响的图表。
图45是显示BzATP之后30分钟,甲氟喹在BV-2小胶质细胞培养物中YO-PRO-3染料摄取的影响的图表。
图46是显示丙磺舒对BV-2小胶质细胞培养物中YO-PRO-3染料摄取的影响的图表。
图47是显示BzATP之后30分钟,丙磺舒对BV-2小胶质细胞培养物中YO-PRO-3染料摄取的影响的图表。
图48是显示甲氟喹和丙磺舒对从纳洛酮刺激的培养的小胶质细胞中收集的ATP水平的影响的图表。
具体实施方式
本公开内容的实施方案涉及用于筛选候选的治疗分子的方法,该治疗分子对于调节哺乳动物中的吗啡戒断症状具有潜在用途。
一个实施方案涉及方法,其中Panx1在脊髓小胶质细胞中被激活以释放作为小胶质细胞-神经元底物的ATP,用于揭示在纳洛酮诱导的戒断期内脊髓LI/II神经元中的长期突触促进。本申请公开了阻断Panx1可有效地减轻吗啡戒断而不影响镇痛。根据本公开的筛选方法对于鉴定能够阻断Panx1活化和/或表达的合适的候选治疗分子尤其有用。
本申请公开的筛选用于调节哺乳动物中的阿片类戒断症状的化合物或组合物的方法的实例包括步骤:
1.选择一组试验动物;
2.将这一组分成两个小组;
3.在两个小组中均诱导Panx1活化或表达;
4.将候选化合物给药至第一小组;
5.将安慰剂给药至第二小组;
6.测量(i)第一小组测试动物的脊髓小胶质细胞,和(ii)第二小组测试动物的脊髓小胶质细胞释放的ATP;
7.对(i)第一小组测试动物的脊髓小胶质细胞和(ii)第二小组测试动物的脊髓小胶质细胞释放的ATP量的差异进行定量;
8.如果第一小组释放的ATP量和第二小组释放的ATP量的差异大于25%,则选择该候选化合物掺入药物组合物中。
在一个实施方案中,本发明提供了用于治疗受试者的阿片类戒断症状的药物组合物,其中所述组合物包含有效量的通过使用本申请公开的方法选择的化合物,所述化合物与合适的稀释剂或载体混合。
根据另一个实施方案,本发明提供了用于治疗受试者的阿片样物质戒断症状的药物组合物,其中所述组合物包含有效量的经选择用于阻断受试者的泛连接蛋白-1通道的化合物。合适的化合物的实例包括10panx肽、甲氟喹、丙磺舒及其组合。
这样的药物组合物可以配制用于病灶内、静脉内、局部、直肠、肠胃外、局部、吸入或皮下、皮内、肌肉内、鞘内、经腹膜、口腔和脑内使用。该组合物可以是液体、固体或半固体形式,例如丸剂、片剂、乳膏、明胶胶囊、胶囊、栓剂、软明胶胶囊、凝胶、膜、小管、溶液或悬浮液。可替代地,该组合物可以在静脉内、腹膜内或皮下注射。或者,该组合物可包含局部递送系统,例如局部乳膏、洗剂、乳剂和透皮贴剂。
本发明的药物组合物可用于对人或动物施用。施用剂量取决于个体需要、所需效果和所选择的施用途径。
本公开的另一个实施方案涉及通过使用本申请公开的方法和/或化合物选择的候选化合物用于改善吗啡戒断症状的用途。合适的剂量水平为5毫克/千克、10毫克/千克、15毫克/千克、20毫克/千克、25毫克/千克、30毫克/千克、35毫克/千克、40毫克/千克、45毫克/千克、50毫克/千克、55毫克/千克、60毫克/千克、65毫克/千克、70毫克/千克、75毫克/千克、80毫克/千克、85毫克/千克、90毫克/千克、95毫克/千克、100毫克/千克,以及介于它们之间的剂量。合适的给药方案是间隔8小时施用,每日施用两次,每日施用一次,以及介于它们之间的给药方案。或者,可以通过缓释透皮贴剂在延长的时间段内提供给药。
本公开的另一个实施方案一般涉及包含一种或多种化合物的组合物,所述化合物经选择用于阻断受试者的泛连接蛋白-1通道,例如10panx肽、甲氟喹、丙磺舒及其组合。合适的剂量水平为5毫克/千克、10毫克/千克、15毫克/千克、20毫克/千克、25毫克/千克、30毫克/千克、35毫克/千克、40毫克/千克、45毫克/千克、50毫克/千克、55毫克/千克、60毫克/千克、65毫克/千克、70毫克/千克、75毫克/千克、80毫克/千克、85毫克/千克、90毫克/千克、95毫克/千克、100毫克/千克,以及介于它们之间的剂量。合适的给药方案是间隔8小时施用,每日施用两次,每日施用一次,以及介于它们之间的给药方案。
所述药物组合物,其包含通过使用本申请公开的方法选择的化合物,或者经选择用于阻断受试者的泛连接蛋白-1通道的化合物,例如10panx肽、甲氟喹、丙磺舒及其组合,其能够通过本身已知的方法制备,制备可施用至患者的药学上可接受的组合物,并使有效量的活性物质与药学上可接受的载体混合成混合物。合适的载体描述于例如雷明顿药物科学(Remington's Pharmaceutical Sciences)(雷明顿药物科学,Mack Publishing Company,Easton,Pa.,USA 1985)中。
例如,本公开的药物组合物,其包含通过使用本申请公开的方法选择的化合物,或者经选择用于阻断受试者的泛连接蛋白-1通道的化合物,例如10panx肽、甲氟喹、丙磺舒及其组合,可以是经配制用于局部施用,或者用于透皮施用以在延长的时间段内提供给药。
用于局部施用的药物组合物可以作为例如软膏、乳膏、悬浮液、洗剂、粉末、溶液、糊剂、凝胶、水凝胶、喷雾剂、气溶胶、敷料或油来提供。当配制成软膏时,活性成分可与石蜡或水混溶性软膏基质一起使用。或者,可以将活性成分配制成具有水包油基质或油包水基质的乳膏。可掺入组合物的其它制剂包括油、栓剂、泡沫、搽剂、气溶胶、口剂和舌下片剂或用于通过皮肤或粘膜吸收的局部装置。
软膏和乳膏可以举例来说用水性或油性基质配制,并加入合适的增稠剂和/或胶凝剂。洗剂可以用水性或油性基质配制,并且通常还含有一种或多种乳化剂、稳定剂、分散剂、悬浮剂、增稠剂或着色剂。液体喷雾剂可方便地从加压包装中递送,例如,通过具有特定形状的封闭物。水包油乳液也可用在所述组合物、贴剂、绷带和制品中。这些体系是半固体乳液、微乳液或泡沫乳液体系。通常这种系统具有“乳白色”外观。含油相可含有但不限于,长链醇(十六烷基、硬脂基)、长链酯(肉豆蔻酸酯、棕榈酸酯、硬脂酸酯)、长链酸(棕榈酸、硬脂酸)、植物和动物油和各种各样的蜡。这些可以用阴离子、阳离子、非离子或两性表面活性剂,或尤其是与非离子表面活性剂组合而制备。本申请仅出于示例性目的提供的一个典型的本发明凝胶基质可含有卵磷脂、棕榈酸异丙酯、泊洛沙姆407和水。具有不同粘度和手感的局部载体是本领域已知的。上述活性成分可以以治疗有效量分散于药学上可接受的载体中,用以治疗神经病和上述其他疾病。
用于透皮施用的药物组合物可以作为例如水凝胶来提供,所述水凝胶包含掺入粘合剂贴剂组合物中的如本申请所述的试剂,所述粘合剂贴剂组合物旨在与受试者的表皮保持长时间的紧密接触。示例性的粘合剂贴剂组合物可包含通过将使用本申请公开的方法选择的化合物或者丙磺舒与硅酮型粘合剂或者丙烯酸酯-乙酸乙烯酯粘合剂在例如二氯甲烷、乙酸乙酯、肉豆蔻酸异丙酯和丙二醇的溶剂中混合而制备的整体层。然后用精密湿膜涂布器将混合物挤出到聚酯-背衬膜上以得到约100微米或更大的均匀厚度。使溶剂在干燥烘箱中蒸发,并将得到的“贴剂”修剪至合适的尺寸。
用于局部施用或者透皮施用如上所述药剂(例如,通过使用本申请公开的方法选择的化合物,或者经选择用于阻断受试者的泛连接蛋白-1通道的化合物,例如10panx肽、甲氟喹、丙磺舒及其组合)的药物可另外掺入渗透增强剂和/或增稠剂或胶凝剂和/或润肤剂和/或抗氧化剂和/或抗微生物防腐剂和/或乳化剂和/或水可混溶的溶剂和/或醇和/或水。
根据一个方面,用于局部施用或透皮施用如上所述药剂(例如通过使用本申请公开的方法选择的化合物,或者经选择用于阻断受试者的泛连接蛋白-1通道的化合物,例如10panx肽、甲氟喹、丙磺舒及其组合)的药物组合物可包含用于透皮或局部递送的一种或多种渗透增强剂或共溶剂。渗透增强剂是有助于活性物质通过角质层扩散的赋形剂。许多渗透增强剂还起到共溶剂的作用,其被认为增加了所述组合物中的通过使用本申请公开的方法选择的化合物,或者经选择用于阻断受试者的泛连接蛋白-1通道的化合物,例如10panx肽、甲氟喹、丙磺舒及其组合的热力学活性或溶解度。渗透增强剂也称为促进剂、佐剂或吸附促进剂。用于本申请所述药物组合物和方法的合适的渗透增强剂应该:(i)具有高效力,具有特定的作用机制;(ii)在施用后表现出快速起效;(iii)有可预测的作用期限;(iv)对皮肤只有非永久性或可逆性的影响;(v)化学上稳定;(vi)没有或具有最小的药理作用;(vii)与其他组合物组分在物理和化学上相容;(viii)无气味;(ix)无色;(x)低变应原的;(xi)无刺激性;(xii)无光毒性;(xiii)非粉刺性;(xiv)具有与皮肤接近的溶解度参数(10.5cal/cm3);(xv)容易获得;(xvi)便宜;(xvii)能够配制成用于局部或透皮递送活性药剂的药物组合物。
具有各种作用机理的几类化合物可用作渗透增强剂。以下列出的渗透增强剂的非限制性实例,其中许多也是合适的共溶剂。亚砜例如二甲基亚砜和癸基甲基亚砜可用作渗透增强剂。二甲基亚砜部分地通过增加脂质流动性和促进药物分配来增强渗透性。相比之下,癸基甲基亚砜通过与皮肤中的蛋白质发生反应,改变蛋白质的构象,导致水性通道的产生,从而增强渗透性。
另一类渗透增强剂是烷酮,例如正庚烷、正辛烷、正壬烷、正癸烷、正十一烷、正十二烷、正十三烷、正十四烷和正十六烷。烷酮被认为通过改变角质层来增强活性剂的渗透性。另一类渗透增强剂是链烷醇,例如乙醇、丙醇、丁醇、2-丁醇、戊醇、2-戊醇、己醇、辛醇、壬醇、癸醇和苄醇。低分子量链烷醇,即具有6个或更少碳原子的那些链烷醇,可能部分地通过充当增溶剂来增强渗透性,而更疏水的醇可以通过从角质层提取脂质来增加扩散。另一类渗透增强剂是脂肪醇,例如油醇、辛醇、癸醇、月桂醇、2-月桂醇、肉豆蔻醇、十六烷醇、硬脂醇、油醇、亚油醇和亚麻醇。多元醇,包括丙二醇、聚乙二醇、乙二醇、二甘醇、三甘醇、二丙二醇、甘油、丙二醇、丁二醇、戊二醇、己三醇、丙二醇单月桂酸酯和二乙二醇单甲醚(二乙二醇单乙醚),也可以增强渗透性。一些多元醇,例如丙二醇,可能通过溶解α-角蛋白和占据氢键位点而起到渗透增强剂的作用,从而减少与活性组织结合的量。
另一类渗透增强剂是酰胺,包括尿素、二甲基乙酰胺、二乙基甲苯酰胺、二甲基甲酰胺、二甲基辛酰胺、二甲基癸酰胺和可生物降解的环状脲(例如1-烷基-4-咪唑啉-2-酮)。酰胺具有增强渗透性的多种机制。例如,一些酰胺如尿素能增加角质层的水合作用,起角质软化作用并产生亲水扩散通道。相比之下,其他酰胺,例如二甲基乙酰胺和二甲基甲酰胺,在低浓度下增加与角蛋白的分配作用,同时增加脂质流动性,并在较高浓度下破坏脂质包装。另一类渗透增强剂是吡咯烷酮衍生物,例如1-甲基-2-吡咯烷酮、2-吡咯烷酮、1-月桂基-2-吡咯烷酮、1-甲基-4-羧基-2-吡咯烷酮、1-己基-4-羧基-2-吡咯烷酮、1-月桂基-4-羧基-2-吡咯烷酮、1-甲基-4-甲氧基羰基-2-吡咯烷酮、1-己基-4-甲氧基羰基-2-吡咯烷酮、1-月桂基-4-甲氧基羰基-2-吡咯烷酮、N-甲基吡咯烷酮、N-环己基吡咯烷酮、N-二甲基氨基丙基吡咯烷酮、N-椰油烷基吡咯烷酮和N-牛脂烷基吡咯烷酮,以及可生物降解的吡咯烷酮衍生物,包括N-(2-羟乙基)-2-的吡咯烷酮脂肪酸酯。部分地,吡咯烷酮衍生物通过与角质层中的角蛋白和皮肤结构中的脂质相互作用来增强渗透性。另一类渗透增强剂是环酰胺,包括1-十二烷基氮杂环庚烷-2-酮,也称为(AZONE是Echo TherapueticsInc.,Philadelphia,PA,USA的注册商标),1-香叶基氮杂环庚烷-2-酮、1-金合欢基氮杂环庚烷-2-酮、1-香叶基香叶基氮杂环庚烷-2-酮、1-(3,7-二甲基辛基)-氮杂环庚烷-2-酮、1-(3,7,11-三甲基十二烷基)氮杂环庚烷-2-酮、1-香叶基氮杂环己烷-2-酮、1-香叶基氮杂环戊烷-2,5-二酮和1-法尼基氮杂环戊烷-2-酮。环酰胺,如可部分通过影响角质层的脂质结构,进而增加分配和增加膜的流动性来增强活性剂的渗透性。
另外一类渗透增强剂包括二乙醇胺、三乙醇胺和六亚甲基月桂酰胺及其衍生物。
另外的渗透增强剂包括直链脂肪酸,例如辛酸、亚油酸、戊酸、庚酸、壬酸、己酸、癸酸、月桂酸、肉豆蔻酸、硬脂酸、油酸和辛酸。线性脂肪酸部分地通过细胞间脂质双分子层的选择性扰动来增强渗透性。此外,一些线性脂肪酸,例如油酸,通过降低脂质的相变温度来增强渗透性,从而增加脂质的运动自由度或流动性。支链脂肪酸,包括异戊酸、新戊酸、新庚酸、壬酸、三甲基己酸、新癸酸和异硬脂酸,是另外的一类渗透增强剂。另一类渗透增强剂是脂肪族脂肪酸酯,例如油酸乙酯、正丁酸异丙酯、正己酸异丙酯、正癸酸异丙酯、肉豆蔻酸异丙酯(“IPM”)、棕榈酸异丙酯和肉豆蔻酸辛基十二烷基酯。脂肪族脂肪酸酯通过增加角质层中的扩散性和/或分配系数来增强渗透性。此外,某些脂肪族脂肪酸酯,例如IPM,通过直接作用于角质层并渗透到脂质体双分子层中从而增加流动性进而增强渗透性。烷基脂肪酸酯,例如乙酸乙酯、乙酸丁酯、乙酸甲酯、戊酸甲酯、丙酸甲酯、癸二酸二乙酯、油酸乙酯、硬脂酸丁酯和月桂酸甲酯,可用作渗透增强剂。烷基脂肪酸酯部分地通过增加脂质流动性来增强渗透性。
另一类渗透增强剂是阴离子表面活性剂,包括月桂酸钠、十二烷基硫酸钠和辛基硫酸钠。阴离子表面活性剂通过改变角质层的屏障功能并允许除去通常用作增塑剂的水溶性试剂来增强活性剂的渗透性。另一类渗透增强剂是阳离子表面活性剂,例如十六烷基三甲基溴化铵、十四烷基三甲基铵、辛基三甲基溴化铵、苯扎氯铵、十八烷基三甲基氯化铵、氯化十六烷基吡啶、十二烷基三甲基氯化铵和十六烷基三甲基氯化铵。阳离子表面活性剂通过吸附生物膜的界面并与其相互作用来增强渗透性,导致皮肤损伤。另一类渗透增强剂是两性离子表面活性剂,例如十六烷基三甲基氨基丙磺酸盐、油基甜菜碱、椰油酰胺丙基羟基磺基甜菜碱和椰油酰胺丙基甜菜碱。非离子表面活性剂,例如Polyxamer 231、Polyxamer182、Polyxamer 184、Polysorbate 20、Polysorbate 60、30、93、96、99(BRIJ是Brij Image&Information Inc.,Greensboro,NC,USA的注册商标)、20、40、60,80、85(SPAN是CrodaInternational PLC,East Yorkshire,UK的注册商标)、20、40、60、80(TWEEN是Uniqema Americas LLC,Wilmington,DE,USA的注册商标)、Myrj 45、51、(MYRJ是Uniqema Americas LLC,Wilmington,DE,USA的注册商标)和840(MIGLYOL是Cremer Oleo GMBH&Co.,Hamburg,Fed.Rep.Germany的注册商标)等等。非离子表面活性剂部分地通过乳化皮脂和增强活性物质的热力学活性或溶解度来增强渗透性。
另一类渗透增强剂增加了活性物质的热力学活性或溶解度,其包括但不限于正辛醇、油酸钠、D-柠檬烯、单油酸甘油酯、桉油醇、油酸油酯和肉豆蔻酸异丙酯。
其他渗透增强剂是胆汁盐,例如胆酸钠、牛磺胆酸的钠盐、乙醇酸和脱氧胆酸。卵磷脂也被发现具有渗透增强的特性。另一类渗透增强剂是萜烯,其包括烃,例如d-柠檬烯、α-蒎烯和β-蒈烯;醇类,如α-萜品醇、松油烯-4-醇和葛缕醇;酮类,如香芹酮、长叶薄荷酮、胡椒酮和薄荷酮;氧化物,如氧化环己烯、氧化柠檬烯、α-蒎烯氧化物、氧化环戊烯和1,8-桉树脑;和油类,如依兰精油、茴香油、藜油和桉树油。萜烯部分地是通过破坏细胞间脂质双分子层,以增加角质层内和角质层上的活性物质的扩散性并打开其极性通道进而增强渗透性。有机酸,例如水杨酸和水杨酸酯(包括它们的甲基、乙基和丙基乙二醇衍生物)、柠檬酸和琥珀酸,是渗透增强剂。另一类渗透增强剂是环糊精,包括2-羟丙基-β-环糊精和2,6-二甲基-β-环糊精。环糊精通过与亲脂性活性物质形成包合物并增加它们在水溶液中的溶解度来增强活性剂的渗透性。
渗透增强剂和/或共溶剂存在于药物组合物中,用于如上所述的药剂(例如,通过使用本申请公开的方法选择的化合物,或者丙磺舒)的局部施用或透皮施用,其量足以提供通过角质层和表皮的所需药物转运水平,或足以增加通过使用本申请公开的方法选择的化合物或者丙磺舒的热力学活性或溶解度。一种或多种药学上可接受的渗透增强剂和/或共溶剂可以以总量的以重量计约0.1%、约0.2%、约0.3%、约0.4%、约0.5%、约0.6%、约0.7%、约0.8%、约0.9%、约1.0%、约1.1%、约1.2%、约1.3%、约1.4%、约1.5%、约1.6%、约1.7%、约1.8%、约1.9%、约2.0%、约2.1%、约2.2%、约2.3%、约2.4%、约2.5%、约2.6%、约2.7%、约2.8%、约2.9%、约3.0%、约3.1%、约3.2%、约3.3%、约3.4%、约3.5%、约3.6%、约3.7%、约3.8%、约3.9%、约4.0%、约4.1%、约4.2%、约4.3%、约4.4%、约4.5%、约4.6%、约4.7%、约4.8%、约4.9%、约5.0%、约5.1%、约5.2%、约5.3%、约5.4%、约5.5%、约5.6%、约5.7%、约5.8%、约5.9%、约6.0%、约6.1%、约6.2%、约6.3%、约6.4%、约6.5%、约6.6%、约6.7%、约6.8%、约6.9%、约7.0%、约7.1%、约7.2%、约7.3%、约7.4%、约7.5%、约7.6%、约7.7%、约7.8%、约7.9%、约8.0%、约8.1%、约8.2%、约8.3%、约8.4%、约8.5%、约8.6%、约8.7%、约8.8%、%约8.9%、约9.0%、约9.1%、约9.2%、约9.3%、约9.4%、约9.5%、约9.6%、约9.7、约9.8%、约9.9%或约10%、约11%、约12%、约13%、约14%、约15%、约16%、约17%、约18%、约1%、约20%、约21%、约22%、约23%、约24%、约25%、约26%、约27%、约28%、约29%、约30%、约31%、约32%、约33%、约34%、约35%、约36%、约37%、约38%、约39%、约40%、约41%、约42%、约43%、约44%、约45%、约46%、约47%、约48%、约49%、约50%、约51%、约52%、约53%、约54%、约55%、约56%、约57%、约58%、约59%、约60%、约61%、约62%、约63%、约64%、约65%、约66%、约67%、约68%、约69%、约70%、约71%、约72%、约73%、约74%、约75%、约76%、约77%、约78%、约79%、约80%、约81%、约82%、约83%、约84%、约85%、约86%、约87%、约88%、约89%、约90%、约91%、约92%、约93%、约94%或约95%的量存在。
所选择的渗透增强剂应该是药理学上惰性的、无毒的和非过敏性的,具有快速和可逆的起效作用,并且与本发明的组合物相容。渗透增强剂的实例的例子有transcutol P、乙醇、异丙醇、月桂醇、水杨酸、辛基苯基聚乙二醇、聚乙二醇400、丙二醇、N-癸基甲基亚砜、DMSO和氮杂环化合物。
在一个示例性实施方案中,本公开内容涉及组合物,其用于局部施用通过使用本申请公开的方法选择的化合物,或者经选择用于阻断受试者的泛连接蛋白-1通道的化合物,例如10panx肽、甲氟喹、丙磺舒,及其组合,其配药剂量足以治疗周围神经病。如本申请所用,术语“局部”是指施用部位附近的有限区域,通常是皮肤处或皮肤附近的神经,包括表皮、真皮、皮区等,皮肤之外的全身渗透是没有的或者受限的。
优选地,局部递送被设计成使药物通过角质层并进入表皮或真皮或皮区的递送最大化,和进入循环系统的吸收最小化。更优选的是可用于局部制剂中以防止活性成分或赋形剂进入下表皮层的试剂。这些所谓的皮肤阻滞剂已经容易地被开发用于许多非处方(OTC)皮肤制剂,例如防晒剂和杀虫剂,其中作用部位限于皮肤表面或上表皮层。在渗透增强或阻滞领域的研究对增强剂和阻滞剂的结构-活性关系产生了有价值的见解(Asbill等,2000,Percutaneous penetration enhancers:local versus transdermalactivity.Pharm.Sci.Tech.Today,3(1):36-41;Kaushik等,2008,Percutaneouspermeation modifiers:enhancement versus retardation.Exp.Opin.Drug Del.5(5):517-529;Trommer等,2006,Overcoming the Stratum Corneum:The Modulation of SkinPenetration.Skin Pharmacol.Physiol.19:106-121),包括诸如酮咯酸硬脂酸酯、氨基己内酰胺类似物、二羧酸酯、柠檬酸钠等化合物。
本文所描述的组合物可进一步包含通常掺入这些制剂中的组分。例如,该组合物还可包含其他成分,例如其他载体、保湿剂、油类、脂肪、蜡、表面活性剂、增稠剂、抗氧化剂、粘度稳定剂、螯合剂、缓冲剂、防腐剂、香料、染料、低级链烷醇、保湿剂、润肤剂、分散剂、防晒剂如辐射阻断化合物或特别地是紫外线阻断剂、抗菌剂、抗真菌剂、消毒剂、维生素、抗生素或其他抗痤疮剂,以及对局部组合物活性没有显著不利影响的其他合适材料。包含在载体中的其他成分是酸式磷酸钠保湿剂、金缕梅提取物载体、甘油保湿剂、杏仁油润肤剂、玉米油分散剂等,其将在下面进一步详述。本领域技术人员将容易地认识到可以在本申请所述的组合物中掺入的其他成分。
根据另一方面,用于局部施用或透皮施用通过使用本申请公开的方法选择的化合物或者丙磺舒的药物组合物可包含适用于本申请所述的组合物和方法的增稠剂或胶凝剂以增加组合物的粘度。合适的试剂(也称为胶凝剂)是示例性的中和的阴离子聚合物或中和的卡波姆,例如聚丙烯酸、羧基聚亚甲基、羧甲基纤维素等,包括Ultrez 10的衍生物,聚合物,例如940、941、954、980、981、ETD2001、EZ-2和EZ-3。(CARBOPOL是LubrizolAdvanced Materials Inc.,Cleveland,OH,USA的注册商标)。如本申请所用,“中和的卡波姆”是合成的高分子量聚合物,主要由中和的聚丙烯酸组成。进一步地,当加入碱以中和卡波姆溶液时,溶液的粘度增加。其他已知的聚合物增稠剂也是合适的,例如聚合物乳化剂、聚卡波非(PEMULEN和NOVEON是Lubrizol AdvancedMaterials Inc.的注册商标)和(KLUCEL是Hercules Inc.,Wilmington,DE,USA的注册商标)。另外的增稠剂、增强剂和佐剂通常可以在Remington的The Science andPractice of Pharmacy以及Handbook of Pharmaceutical Excipients(Arthur H.Kibbeed.2000)中找到。或者,用于局部施用或透皮施用通过使用本申请公开的方法选择的化合物或者丙磺舒的药物组合物可以包含阴离子聚合物增稠剂前体,例如卡波姆,其已经与中和剂结合,其中中和剂用量足以形成粘度大于1000cps的凝胶或凝胶状组合物,所述粘度用Brookfield RV DVII+粘度计测量,锭子CPE-52,扭矩大于10%和温度保持在25℃。或者,阴离子聚合物增稠剂前体可以与选自下组的中和剂结合:氢氧化钠、氢氧化铵、氢氧化钾、精氨酸、氨基甲基丙醇、四羟丙基乙二胺、三乙醇胺(“TEA”)、氨基丁三醇、PEG-15椰油胺、二异丙醇胺和三异丙醇胺,或其组合,其中中和剂用量足以中和阴离子聚合物增稠剂前体,以在形成组合物的过程中形成凝胶或凝胶状组合物。增稠剂或胶凝剂的存在量足以提供组合物所需的流变性质,包括具有足够的粘度以形成可应用于哺乳动物皮肤的凝胶或凝胶状组合物。总量中增稠剂或胶凝剂的含量以重量计为约0.1%、约0.25%、约0.5%、约0.75%、约1%、约1.25%、约1.5%、约1.75%、约2.0%、约2.25%、约2.5%、约2.75%、约3.0%、约3.25%、约3.5%、约3.75%、约4.0%、约4.25%、约4.5%、约4.75%、约5.0%、约5.25%、约5.5%、约5.75%、约6.0%、约6.25%、约6.5%、约6.75%、约7.0%、约7.25%、约7.5%、约7.75%、约8.0%、约8.25%、约8.5%、约8.75%、约9.0%、约9.25%、约9.5%、约9.75%、约10%、约11%、约11.5%、约12%、约12.5%、约13%、约13.5%、约14%、约14.5%或约15%,以及它们之间。
根据另一方面,用于局部施用或透皮施用通过使用本申请公开的方法选择的化合物,或者经选择用于阻断受试者的泛连接蛋白-1通道的化合物,例如10panx肽、甲氟喹、丙磺舒及其组合的药物组合物可包含润肤剂。合适的润肤剂的例子有矿物油、矿物油和羊毛脂醇的混合物、鲸蜡醇、十六十八醇、凡士林、凡士林和羊毛脂醇、十六烷基酯蜡、胆固醇、甘油、单硬脂酸甘油酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、卵磷脂、己酸丙烯酯、药蜀葵提取物、花生醇、argobase EUC、丁二醇、二辛酸酯/二癸酸酯、阿拉伯胶、尿囊素、角叉菜胶、十六烷基二甲基聚硅氧烷、环甲基硅油、琥珀酸二乙酯、二氢枞醇山嵛酸酯、己二酸二辛酯、月桂酸乙酯、棕榈酸乙酯、硬脂酸乙酯、月桂酸异戊酯、辛酸酯、PEG-75、羊毛脂、山梨糖醇月桂酸酯、核桃油、小麦胚芽油、超精制杏仁、超精制芝麻、超精制大豆、棕榈酸辛酯、辛酸/癸酸甘油三酯和甘油基椰油酸酯。如果存在的话,润肤剂在本申请所述的组合物中的存在量为组合物重量的约1%至约30%、约3%至约25%,或约5%至约15%。说明性地,一种或多种润肤剂的总量为以重量计约1%、约2%、约3%、约4%、约5%、约6%、约7%、约8%、约9%、约10%、约11%、约12%、约13%、约14%、约1%、约16%、约17%、约18%、约19%、约20%、约21%、约22%、约23%、约24%、约25%、约26%、约27%、约28%、约29%或约30%,以及它们之间。
根据另一方面,用于局部施用或透皮施用通过使用本申请公开的方法选择的化合物,或者经选择用于阻断受试者的泛连接蛋白-1通道的化合物,例如10panx肽、甲氟喹、丙磺舒及其组合的药物组合物可包含抗氧化剂。合适的抗氧化剂的例子有柠檬酸、丁基化羟基甲苯(BHT)、抗坏血酸、谷胱甘肽、视黄醇、α-生育酚、β-胡萝卜素、α-胡萝卜素、泛醌、丁基羟基茴香醚、乙二胺四乙酸、硒、锌、木脂素、尿酸、硫辛酸和N-乙酰半胱氨酸。如果存在的话,抗氧化剂在本申请所述的组合物中以总量的以重量计选自约0.025%至约1.0%的量存在。
根据另一方面,用于局部施用或透皮施用通过使用本申请公开的方法选择的化合物,或者经选择用于阻断受试者的泛连接蛋白-1通道的化合物,例如10panx肽、甲氟喹、丙磺舒,及其组合的药物组合物可包含抗微生物防腐剂。示例性抗微生物防腐剂包括酸,包括但不限于苯甲酸、酚酸、山梨酸、醇、苄索氯铵、溴硝丙二醇、对羟基苯甲酸丁酯、溴棕三甲铵、氯己定、氯丁醇、氯甲酚、甲酚、对羟基苯甲酸乙酯、咪唑烷基脲、对羟基苯甲酸甲酯、苯酚、苯氧乙醇、苯乙醇、醋酸苯汞、硼酸苯汞、硝酸苯汞、山梨酸钾、对羟基苯甲酸丙酯、丙酸钠或硫柳汞。如果存在,抗微生物防腐剂以组合物重量的约0.1%至约5%、约0.2%至约3%,或约0.3%至约2%,例如约0.2%、约0.4%、约0.6%、约0.8%、约1%、约1.2%、约1.4%、约1.6%、约1.8%、约2%、约2.2%、约2.4%、约2.6%、约2.8%、约3.0%、约3.2%、约3.4%、约3.6%、约3.8%、约4%、约4.2%、约4.4%、约4.6%、约4.8%或约5%的量存在。
根据另一方面,用于局部施用或透皮施用通过使用本申请公开的方法选择的化合物,或者经选择用于阻断受试者的泛连接蛋白-1通道的化合物,例如10panx肽、甲氟喹、丙磺舒及其组合的药物组合物可包含一种或多种乳化剂。术语“乳化剂”是指能够降低非极性相和极性相之间的表面张力的试剂,并且包括自乳化剂。合适的乳化剂可以来自任何类型的药学上可接受的乳化剂,例如碳水化合物、蛋白质、高分子量醇、润湿剂、蜡和细碎固体。如果存在,任选的乳化剂在组合物中的存在量为组合物重量的约1%至约25%、约1%至约20%,或约1%至约15%。说明性地,一种或多种乳化剂在总量中以重量计为约1%、约2%、约3%、约4%、约5%、约6%、约7%、约8%、约9%、约10%、约11%、约12%、约13%、约14%、约15%、约16%、约17%、约18%、约19%、约20%、约21%、约22%、约23%、约24%或约25%。
根据另一方面,用于局部施用或透皮施用通过使用本申请公开的方法选择的化合物,或者经选择用于阻断受试者的泛连接蛋白-1通道的化合物,例如10panx肽、甲氟喹、丙磺舒及其组合的药物组合物可包含水混溶性溶剂,例如丙二醇。合适的水混溶性溶剂是指可用于药物组合物并且可与水混溶的任何溶剂。如果存在,水混溶性溶剂在组合物中的总量以重量计为组合物的约1%至约95%、约2%至约75%、约3%至约50%、约4%至约40%,或约5%至约25%。
根据另一方面,用于局部施用或透皮施用通过使用本申请公开的方法选择的化合物,或者经选择用于阻断受试者的泛连接蛋白-1通道的化合物,例如10panx肽、甲氟喹、丙磺舒及其组合的药物组合物可包含一种或多种醇。在进一步的实施方案中,醇是低级醇。如本申请所用,术语“低级醇”,单独地或组合地,是指含有一至约六个碳原子的直链或支链醇部分。在一个实施方案中,低级醇含有一个至约四个碳原子,而在另一个实施方案中,低级醇含有两个或三个碳原子。这种醇部分的实例包括甲醇、乙醇、乙醇USP(即95%v/v)、正丙醇、异丙醇、正丁醇、异丁醇、仲丁醇和叔丁醇。如本申请所用,术语“乙醇”是指C2H5OH。它可以用作脱水醇USP、醇USP或包括与各种量的水相组合的任何常见形式。如果存在,醇的存在量足以形成适于与哺乳动物接触的组合物。例如,占总量的以重量计约1%、约2%、约3%、约4%、约5%、约6%、约7%、约8%、约9%、约10%、约11%、约12%、约13%、约14%、约15%、约16%、约17%、约18%、约19%、约20%、约21%、约22%、约23%、约24%、约25%。
另一个实施方案涉及药物组合物,其包含通过使用本申请公开的方法选择的化合物,或者经选择用于阻断受试者的泛连接蛋白-1通道的化合物,例如10panx肽、甲氟喹、丙磺舒及其组合,被配制为通过注射用于肠胃外施用。本公开的可注射药物组合物包含合适的载体溶液,例如无菌水、盐水和生理pH下的缓冲溶液。合适的缓冲溶液的例子有林格氏葡萄糖溶液和林格氏乳酸溶液。载体溶液可包含占总量的以重量计为约0.1%、约0.2%、约0.3%、约0.4%、约0.5%、约0.6%、约0.7%、约0.8%、约0.9%、约1.0%、约1.1%、约1.2%、约1.3%、约1.4%、约1.5%、约1.6%、约1.7%、约1.8%、约1.9%、约2.0%>、约2.1%、约2.2%、约2.3%、约2.4%、约2.5%、约2.6%、约2.7%、约2.8%、约2.9%、约3.0%、约3.1%、约3.2%、约3.3%、约3.4%、约3.5%、约3.6%、约3.7%、约3.8%、约3.9%、约4.0%、约4.1%、约4.2%、约4.3%、约4.4%、约4.5%、约4.6%、约4.7%、约4.8%、约4.9%、约5.0%、约5.1%、约5.2%、约5.3%、约5.4%、约5.5%、约5.6%、约5.7%、约5.8%、约5.9%、约6.0%、约6.1%、约6.2%、约6.3%、约6.4%、约6.5%、约6.6%、约6.7%、约6.8%、约6.9%、约7.0%、约7.1%、约7.2%、约7.3%、约7.4%、约7.5%、约7.6%、约7.7%、约7.8%、约7.9%、约8.0%、约8.1%、约8.2%、约8.3%、约8.4%、约8.5%、约8.6%、约8.7%、约8.8%、约8.9%、约9.0%、约9.1%、约9.2%)、约9.3%、约9.4%、约9.5%、约9.6%、约9.7%、约9.8%、约9.9%或约10%、约11%、约12%、约13%、约14%、约15%、约16%、约17%、约18%、约19%、约20%、约21%、约22%、约23%、约24%、约25%、约26%、约27%、约28%、约29%、约30%、约31%、约32%、约33%、约34%、约35%、约36%、约37%、约38%、约39%、约40%、约41%、约42%、约43%、约44%、约45%、约46%、约47%、约48%、约49%、约50%、约51%、约52%、约53%、约54%、约55%、约56%、约57%、约58%、约59%、约60%、约61%、约62%、约63%、约64%、约65%、约66%、约67%、约68%、约69%、约70%、约71%、约72%、约73%、约74%、大约75%、约76%、约77%、约78%、约79%、约80%、约81%、约82%、约83%、约84%、约85%、约86%、约87%、约88%、约89%、约90%、约91%、约92%、约93%、约94%或约95%。
根据一个方面,可注射药物组合物可另外掺入一种或多种非水溶剂,例如丙二醇、聚乙二醇、植物油如橄榄油,和可注射的有机酯如油酸乙酯。
根据另一方面,可注射药物组合物可另外掺入一种或多种抗微生物剂、抗氧化剂、螯合剂等。
可注射药物组合物可以在单位剂量或多剂量容器中存在,例如密封的安瓿和小瓶。可注射药物组合物可以在冷冻干燥(冻干)条件下储存,用于注射时需要在使用前立即加入无菌液体载体,例如无菌盐水溶液。
另一个实施方案涉及药物组合物,其包含通过使用本申请公开的方法选择的化合物,或者经选择用于阻断受试者的泛连接蛋白-1通道的化合物,例如10panx肽、甲氟喹、丙磺舒及其组合,被配制用于口服施用。口服药物组合物可以胶囊或片剂形式;以粉末或颗粒;以溶液、糖浆或悬浮液(在含水或非含水的液体中)提供。片剂或硬明胶胶囊可包含例如乳糖、淀粉或其衍生物、硬脂酸镁、糖精钠、纤维素、碳酸镁、硬脂酸或其盐。软明胶胶囊可包含例如植物油、蜡、脂肪、半固体或液体多元醇等。溶液和糖浆可包含例如水、多元醇和糖。通过使用本申请公开的方法而选择的化合物,或者丙磺舒,可以用延迟崩解或影响活性剂在胃肠道中吸收的材料(例如,单硬脂酸甘油酯或二硬脂酸甘油酯)包被或与之混合。因此,例如,可以在多个小时内实现活性剂的持续释放,并且如果需要,可以保护活性剂使之免于在胃肠道内降解。利用沿胃肠道的各种pH和酶的条件,可以配制用于口服施用的药物组合物,以促进活性剂在特定胃肠位置的释放。
提供以下实施例以更全面地描述本公开内容,并且是出于非限制性的说明性目的而给出。
实施例
在本申请公开的实施例中使用以下方法和材料。
动物:
使用成年雄性大鼠和小鼠(7-8周龄的大鼠;6-10周龄的小鼠)。将小鼠和大鼠圈养在12小时/12小时的光照/黑暗循环中,可随意获取食物和水。所有实验均经卡尔加里大学和拉瓦尔大学动物护理委员会批准,并符合加拿大动物保护协会的指导原则。
吗啡剂量范式和伤害性行为模型:
在0.9%无菌盐水溶液中制备的硫酸吗啡(PCCA)每日两次(上午8点和下午5点)腹膜内注射到Sprague-Dawley大鼠(从10至45毫克/千克逐步增加剂量),Cx3cr1-cre::Pnx1flx/flx,或Pnx1flx/flx小鼠(从7.5至50毫克/千克逐步增加剂量)。使用甩尾试验(大鼠)和尾部浸泡试验(小鼠)评估热伤害感受阈值。对于大鼠,将红外热刺激(Ugo Basile)应用于尾部的腹侧表面,并记录从刺激中移出尾部的等待时间。对于小鼠,将尾部的远端部分浸没在50℃的水浴中,并记录从刺激中移出尾部的等待时间。最大截止时间设定为10秒以防止组织损伤。在注射之前和吗啡注射之后30分钟进行伤害感受测量,并将所得数值标准化为每日基线。在一部分小鼠实验中,在单次急性注射吗啡(7.5毫克/千克)后的30分钟、45分钟、60分钟、120分钟和180分钟执行吗啡诱导的抗伤害感受的时间过程。
纳洛酮催促吗啡戒断的行为评估:
大鼠和小鼠以8小时为间隔于腹膜内接受递增剂量的吗啡(大鼠:第1天,每公斤10毫克;第2天,每公斤20毫克;第3天,每公斤30毫克;第4天,每公斤40毫克;小鼠:第1天,每公斤7.5和15毫克;第2天,每天20和25毫克;第3天,每天30和35毫克;第4天,每公斤40和45毫克)。在第5天,大鼠和小鼠于早晨接受注射吗啡(大鼠:45毫克/千克;小鼠:50毫克/千克)并在2小时后加以纳洛酮(2毫克/千克)以快速催促戒断。对照大鼠和小鼠接受盐水并在第5天用纳洛酮激发。按照Ferrini等人教导的方法记录戒断的迹象(2013,Morphinehyperalgesia gated through microglia-mediated disruption of neuronal Cl-homeostasis.Nat.Neurosci.16:183–192)。以5分钟的间隔评估跳跃、牙齿颤动、湿狗摇动、摇头和梳理行为,总测试时间为30分钟,并且为每种行为分配0至3的标准化分数。还评估了异常性疼痛、毛发直立、流涎、射精和颤抖/抽搐,其中一点是在每5分钟间隔期间存在所述行为。对所有体征进行计数和编辑以产生累积戒断评分。在纳洛酮激发之前和之后称重大鼠和小鼠以计算体重的减轻。在所有行为研究中,实验者对大鼠和小鼠的药物处理过程和基因型并不知晓。
鞘内药物施用:
在一部分实验中,如Ichikizaki等人(1979,A new procedure for lumbarpuncture in the mouse(intrathecal injection)preliminary report.Keio J.Med.28(4):165-171)所教导的,通过腰椎穿刺法在2%异氟烷(体积/体积)作用下经鞘内注射给大鼠和小鼠施用药物。在早晨吗啡注射前的第1天和第3天注射Mac-1-皂草素和皂草素(20微克,Advanced Targeting Systems)。在纳洛酮催促戒断前1小时鞘内注射10panx(10微克,WRQAAFVDSY)和scrpanx(10微克,FSVYWAQADR),而在纳洛酮之前15分钟鞘内注射腺苷三磷酸双磷酸酶(10单位,Sigma Aldrich)和ARL67156(10纳摩尔,Sigma Aldrich)。在纳洛酮催促戒断之前立即递送ATPγS(100μM,Roche)。所有对照动物均接受鞘内盐水。通过微渗透泵植入(Alzet)对一些大鼠进行鞘内药物递送。用2%异氟烷(体积/体积)麻醉大鼠,并将连接到微渗透泵的导管插入腰段的背鞘内空间。渗透泵从吗啡或盐水处理的第1天至第4天提供连续药物递送(1微升/小时),并且用盐水、10panx(2微克/微升)或scrpanx(2微克/微升)填充。
全身药物施用:
吗啡依赖性大鼠在纳洛酮催促戒断前1小时接受全身甲氟喹(45毫克/千克i.p.,Sigma)或丙磺舒(50毫克/千克i.p.,Sigma)。甲氟喹和丙磺舒均在β-环糊精(Sigma)中重构,而对照动物接受全身β-环糊精。
蛋白质印迹:
快速解剖大鼠脊髓组织并在含有20mM TrisHCl(pH 7.5)、150mM NaCl和0.5%Tween-20的RIPA缓冲液中匀浆。在含有50mM TrisHCl、150mM NaCl、10mM EDTA、0.1%Triton-X和5%甘油的150微升裂解缓冲液中收获培养的小胶质细胞。RIPA和裂解缓冲液均含有蛋白酶抑制剂(Sigma)和磷酸酶抑制剂(GBiosciences)。使用BioRad RC DC蛋白质测定试剂盒(BioRad)或Pierce BCA蛋白质测定试剂盒(Thermo Scientific)测量总蛋白质。将样品在上样缓冲液(350mM Tris、30%甘油、1.6%SDS、1.2%溴酚蓝、6%β-巯基乙醇)中于95℃加热5分钟,然后在预制SDS凝胶上电泳(4-12%Tris-HCl,BioRad)并转移到硝酸纤维素膜上。封闭后,将膜与针对P2X7R的兔抗体(1:300,Alomone,APR008)、针对β-肌动蛋白的小鼠抗体(1:2000,Sigma-Aldrich,A5316)或针对Panx1的兔抗体(1:300,LifeTechnologies,488100;或1:10,000,Abcam,ab124969)一起孵育。洗涤该膜并在20-25℃下在荧光团缀合的二抗中孵育2小时(抗兔和抗小鼠缀合的IR染料1:5000,MandelScientific;或Fluorescent TrueBlot抗兔IgG Dylight 1:1000,Rockland),然后通过直接检测680和800nm处的二抗荧光(LICOR Odyssey CLx)来量化。使用Image J定量条带强度,标准化为β-肌动蛋白并相对于对照样品进行表达。成年的混合的神经元-胶质细胞培养物的分离:
将大鼠和小鼠麻醉并仅用PBS经心脏灌注。分离脊髓和脑(仅小鼠)组织并置于含有10%FBS的PBS中。在钝性解离后,将脊髓内容物通过70微米细胞过滤器过滤到含有10mMHEPES和2%FBS的DMEM中。向细胞悬浮液中加入等渗percoll(密度1.23克/毫升),然后加入1.08克/毫升percoll衬底。将样品在20℃以3,000rpm旋转30分钟。离心后,除去髓磷脂碎片,收集percoll梯度之间的界面并转移到新鲜培养基中。将样品在4℃以1,350rpm再旋转10分钟,并将沉淀物重建在含有10%FBS的PBS中用于流式细胞术或含有10%FBS和1%Pen-Strep的DMEM中用于活细胞成像。
流式细胞术:
按如上所述从成年大鼠脊髓分离混合的神经元-胶质细胞培养物。细胞用抗体Panx1(1:400Pierce,Life Technologies)和荧光团缀合的抗体CD11b/c-PE(1:500eBioscience)在20℃染色1小时。通过声波聚集流式细胞仪(Applied Biosystems)测量细胞荧光。使用前向和侧向散射图对活的单细胞群进行分类。与未染色细胞相比,在单染色细胞中分别地使用BL2和RL1的强度为CD11b和Panx1的正染色进行分类。
BV2小胶质细胞培养:
将BV2小胶质细胞维持在含有10%FBS和1%Pen-Strep的DMEM培养基(Gibco)中,37℃,5%CO2。连续5天每天用吗啡(10μM)或盐水处理细胞一次。
来自出生后大鼠的原代小胶质细胞培养物:
如Trang等人(2009,P2X4-receptor-mediated synthesis and release ofbrain-derived neurotrophic factor in microglia is dependent on calcium andp38-mitogen-activated protein kinase activation.J.Neurosci.18;29(11):3518-3528)所教导的那样制备原代小胶质细胞培养物。简言之,从出生后(P1-P3)SpragueDawley大鼠皮层中分离混合的神经元-胶质细胞培养物,并在含有10%FBS和1%Pen-Strep的DMEM培养基中于37℃和5%CO2下维持10-14天。通过轻轻摇动将小胶质细胞与混合培养物分离。分离后,将小胶质细胞铺板并用吗啡(10μM)或盐水每天处理一次,共处理5天。
钙成像:
将细胞与荧光Ca2+指示剂染料Fura-2AM(2.5μM,Molecular Probes)在含有140mMNaCl、5.4mM KCl、1.3mM CaCl2、10mM HEPES和33mM葡萄糖的细胞外溶液(ECS)(pH 7.35,渗透压315mOsm)中孵育30分钟。所有实验均在室温下使用倒置显微镜(Nikon Eclipse TiC1SI Spectral Confocal)进行,并使用EasyRatioPro软件(PTI)记录单个小胶质细胞的荧光。激发光由氙弧灯产生并交替通过340或380nm带通滤波器(Omega Optical,VT,USA)。在经过基线扣除后计算340/380荧光比率。
繁育Cx3cr1::Panx1flx/flx小鼠:
使用Cre-loxP系统繁育具有小胶质细胞特异性缺失Panx1的小鼠。含有Panx1基因侧翼外显子2的flox序列的Panx1flx/flx纯合小鼠(Weillenger等,2012,Anoxia-inducedNMDA receptor activation opens pannexin channels via Src familykinases.J.Neurosci.32(36):12579--12588)与在Cx3cr1启动子下表达Cre-ER融合蛋白和增强型黄色荧光蛋白(eYFP)的C57BL6/J小鼠杂交(Jax小鼠:B6.129P2(Cg)-Cx3cr1tm2.1(cre /ERT)Litt/WganJ,库存号021160)。使用PCR筛选子代基因型,而且纯合的Panx1flx/flx和Cx3cr1-cre小鼠繁殖并回交8代以产生条件性Cx3cr1::Panx1flx/flx敲除小鼠。为了诱导Cre重组,给小鼠腹膜内注射1毫克/天的他莫昔芬(Sigma)共5天。野生型小鼠是同窝小鼠,其接受载体注射(含10%乙醇的向日葵油)5天,而对于他莫昔芬的相关效应则通过使Panx1flx/flx同窝小鼠接受5天他莫昔芬注射来控制。在大多数实验中,在最终的他莫昔芬注射的7天后进行测试,并且使用与CX3CR1-cre小鼠杂交的Ai14tdTomato报告小鼠(Jax小鼠:B6.Cg-Gt(ROSA)26Sortm14(CAG-tdTomato)Hze/J,库存号007914)来评估7天重组的成功。在一部分实验中,在最终的他莫昔芬注射的28天后进行吗啡戒断的行为评估,以控制外周Cx3cr1表达细胞的效应。
YO-PRO染料摄取:
在5天吗啡或盐水处理后,将BV-2细胞在含YO-PRO-1或YO-PRO-3染料(2.5μM,Invitrogen)的ECS中温育。在5分钟基线记录后,用BzATP(150μM,Sigma)刺激细胞并记录染料摄取30分钟。通过使用离子霉素(1μM,Sigma)记录30分钟后立即评估细胞活力。使用FilterMax F5读板仪(Molecular Devices)在37℃检测YO-PRO-1染料荧光发射(491/509)或YO-PRO-3染料荧光发射(612/631)。使用的药物包括10panx、scrpanx和纳洛酮,所有这些药物都以10μM使用。将药物浸渍于YO-PRO-1染料中,并在基线记录之前在37℃温育10分钟。计算BzATP应用后30分钟的荧光发射相对于基线的百分比变化。使用倒置显微镜(NikonEclipse Ti C1S1Spectral Confocal)在室温下拍摄BV-2YO-PRO-1染料摄取的代表性图像,使用EasyRatioPro软件(PTI)以5分钟为间隔拍摄图像30分钟。为了评估Cx3cr1::Panx1flx/flx成年小胶质细胞中的Panx1功能,从他莫昔芬或载体处理过5天的成年小鼠中分离神经元-胶质混合物培养物,然后接种在含有10%FBS和1%Pen-Strep的DMEM中,并在37℃下、含5%CO2温育过夜。洗涤细胞并与DAPI(1:10,000)一起温育10分钟,然后在YO-PRO-3染料中温育。通过eYFP的内源性表达从混合的成年神经元-胶质细胞培养物中鉴定小胶质细胞。记录5分钟基线期的各个eYFP阳性小胶质细胞的荧光,然后在BzATP刺激(300μM)后记录30分钟。计算30分钟时的荧光发射以及相对于基线的百分比变化。
纳洛酮刺激的ATP释放:
通过将样品与重组萤火虫荧光素酶及其底物D-荧光素(ATP测定试剂盒,LifeTechnologies)相组合,使用生物发光检测ATP水平。将ATP酶抑制剂(ARL67156,1μM,Sigma)加入到ECS或ACSF中以减少ATP的分解,并且在纳洛酮刺激之前将样品在培养基中温育30分钟以减少机械诱导的ATP释放。用纳洛酮(10μM)刺激样品30分钟,此时收集上清液。收集后立即使用FilterMax F5读板器在28℃读取样品。对于BV-2小胶质细胞培养物的实验,在纳洛酮刺激之前,将细胞在10panx(10μM)、scrpanx(10μM)、丙磺舒(1mM)、甲氟喹(40μM)或ECS中孵育10分钟。用相对于来自相同平板的对照样品(盐水处理和ECS刺激)表示最终ATP的测量值。对于脊髓切片中的ATP释放,用冰冷的充氧蔗糖取代的ACSF来灌注他莫昔芬或载体处理过的Cx3cr1::Panx1flx/flx小鼠,并通过水力挤压分离出脊髓。将脊髓的腰段切成300μm的切片,并在充氧的37℃ACSF中孵育1小时。然后将脊髓切片转移至室温的充氧的ACSF中并用纳洛酮刺激。为了定量,根据每个样品的总蛋白将ATP的释放进行标准化。
组织学程序:
用戊巴比妥(Bimeda-MTC Animal Health Inc.)麻醉大鼠和小鼠,并用4%多聚甲醛(PFA)(wt/vol)经心脏灌注。解剖后,将脊柱腰段在4%PFA中进行后固定,然后在30%蔗糖中冷冻保存。将脊髓切成30μm的自由漂浮切片,然后在4℃下在针对CD11b的小鼠抗体(1:50,CBL1512EMD Milipore)、CD11b的大鼠抗体(1:500,Abeam,ab64347)或抗GFP的兔抗体(1:400,Life Technologies,A-6465)中过夜孵育。然后洗涤切片并在4℃下与荧光染料偶联的二抗(1:1000,Cy3-缀合的驴抗小鼠IgG,Jackson Immuno Research;1:100,Cy5-缀合的驴抗兔IgG,Jackson Immuno Research;或1:2000驴抗大鼠IgG AlexaFluor 555,Abcam,ab150154)孵育。使用Nikon Eclipse Ti C1SI光谱共聚焦显微镜拍摄图像。使用Image J(NIH)进行定量,实验者对基因型和/或药物处理过程并不知晓。
c-Fos免疫标记:
按如上所述分离小鼠脊髓组织并切片。将自由漂浮的脊髓切片用0.3%H2O2封闭10分钟,然后用1%NaBH4封闭5分钟。将切片在4℃下与针对cFos的兔抗体(1:5000,Abcam,ab7963)一起温育过夜。将切片洗涤并在生物素化的抗兔二抗(1:1000;VectorLaboratories Inc.)中孵育2小时,然后用Vecastain ABC试剂盒(Vector LaboratoriesInc.)处理,并用3,3-二氨基联苯胺与镍一起显色1分钟。使用Olympus Virtual SlideSystem Macro Slide Scanner拍摄图像,并对浅表脊髓背角内的Fos-免疫反应细胞的数量进行计数。由不知晓基因型和药物处理过程的实验者进行摄像和定量。
离体脊髓记录:
如Bonin等人(2014,A spinal analog of memory reconsolidation enablesreversal of hyperalgesia.Nat.Neurosci.;17(8):1043-5)所教导的,记录浅表背角中的电诱发场电位。用氨基甲酸乙酯(2克/千克)麻醉动物并用冰冷的充氧的(95%O2,5%CO2)蔗糖为基础的人工脑脊髓液(S-aCSF)短暂灌注心包,所述人工脑脊髓液含有以下物质(以mM计)的:252蔗糖、2.5KCl、6MgCl2、1.5CaCl2、1.25NaH2PO4、26NaHCO3、4犬尿喹啉酸和10D-葡萄糖。迅速取出腰椎柱并浸入冰冷的S-ACSF中,通过椎板切除术获得脊髓。使脊髓外植体在含有充氧的(95%O2,5%CO2)aCSF(126NaCl、2.5KCl、2MgCl2、2CaCl2、1.25NaH2PO4、26NaHCO3和10D-葡萄糖)的浸没室中于室温下恢复30分钟。
通过在背根入口区插入脊髓外植体背侧的硼硅酸盐玻璃电极记录突触后场电位(fPSPs)。用MPC-200操纵器(Sutter Instrument Company,Novato,CA,USA)测量,将电极表面插入距离脊髓背面不超过125μm的深度。当填充aCSF时,电极具有3-4MΩ的尖端电阻。使用置于背根切口端附近的aCSF填充的硼硅酸盐吸力电极,通过电刺激背根引起fPSPs。用Multiclamp 700B放大器(Molecular Devices,Sunnyvale,CA,USA)扩增场电位,用Digidata 1322A(Molecular Devices)数字化,并用pClamp 10软件(Molecular Devices)记录。在采集期间使用设置为1.6kHz的低通滤波器对数据进行滤波,并以10kHz频率采样。每60秒提供测试刺激以引起fPSPs,并且基线被确定为30分钟的稳定响应期(小于15%的可变性)。在观察到稳定的基线后,通过浴的方式施加纳洛酮(10μM)或以2Hz频率刺激2分钟来诱发LTP,其强度比基线刺激高25%,之后将刺激重新调整至基线水平,并且每分钟再发送一次测试脉冲。使用ClampFit 10软件(Molecular Devices)分析数据。在fPSP发起后0-800ms测量fPSPs相对于基线的面积。
统计:
所有数据表示为平均值±s.e.m.。使用非配对t检验(2侧)或具有事后Bonferroni或Sidak检验的普通单向ANOVA进行统计学差异的测试。使用具有事后Sidak检验的双向重复测量ANOVA来分析时间过程和每日抗伤害感受实验。样本量与类似研究中报告的样本量一致。对于所有实验,标准水平设定为0.05。
通过在5天内每天两次全身施用吗啡硫酸盐,在大鼠中建立吗啡的身体依赖性(图1)。在第5天,注射阿片受体拮抗剂纳洛酮(2m/kg,腹膜内注射)在吗啡处理的大鼠中催促出一系列戒断症状;当向盐水对照大鼠施用纳洛酮时未观察到这些迹象(图2、3)。吗啡施用增加了脊髓背角的CD11b免疫反应性,表明脊髓小胶质细胞对吗啡处理有反应(图4、5)。为了测试脊髓小胶质细胞是否有助于吗啡戒断,鞘内注射的皂草素缀合的抗体Mac1(Mac1-saporin;20微克)以耗尽吗啡处理的大鼠脊髓中的小胶质细胞(图1)。小胶质细胞的耗尽局限于脊髓的腰椎注射部位(图4、5),并且没有改变对吗啡的时间过程或峰值抗伤害性反应(图6)。因此,在Mac1-皂草素处理后,吗啡抗伤害感受保持完整。相比之下,Mac1-皂草素,但不是非缀合的皂草素对照组,显著减弱了纳洛酮催促的戒断行为(图2)。这些结果表明脊髓小胶质细胞对吗啡戒断有至关重要的贡献。
在脊髓中,与盐水处理的大鼠相比,吗啡处理的大鼠中的Panx1蛋白表达显著地更高(图7)。流式细胞术分析表明,吗啡诱导的增加发生在CD11b阳性细胞中(图8、9),表明增加的Panx1表达是小胶质细胞特异性的。为了确定吗啡是否直接作用于小胶质细胞以调节Panxl表达,大鼠原代小神经胶质细胞培养物和BV-2小胶质细胞系均用吗啡分别处理5天,并发现这两个细胞培养系统中的总Panxl蛋白水平显著增加(图10、11)。通过测量BzATP诱发的大分子量染料YO-PRO-1的摄取来评估吗啡处理对Panx1活性的影响。与盐水处理的小胶质细胞相比,BzATP(150μM)引起吗啡处理的小胶质细胞中YO-PRO-1显著地更大的摄取(图12、13、14)。在吗啡处理的细胞中,在纳洛酮(10μM)存在下进一步增强YO-PRO-1摄取(图12、13、14)并且被小肽Panx1抑制剂10panx(10μM)阻断,但不受乱序肽scrpanx的影响(图15、16)。因此,确定吗啡处理在小胶质细胞中自主地上调Panx1的表达和活性。
纳洛酮在吗啡处理的小胶质细胞中增强Panx1活性的观察结果表明,Panxl可能有助于纳洛酮诱导的吗啡戒断行为。这是通过给经5天吗啡处理后具有建立的躯体依赖性的大鼠鞘内施用10panx(10μM)而测定的。在纳洛酮激发前60分钟施用10panx显著减弱了戒断行为,表明必需的Panx1在小胶质细胞上表达。用他莫昔芬诱导CX3CR1表达细胞中的Panx1缺失繁育转基因小鼠(Cx3cr1-cre::Panx1flx/flx)。这些转基因小鼠用于证实CreER报道子eYFP定位于腰部脊髓中的CD11b阳性细胞(图18),并且在他莫昔芬处理7天后,在95±3.1%的这些细胞中存在重组(图19、20)。此外,从缺乏Panx1的成年小鼠(注射他莫昔芬的Cx3cr1-cre::Panx1flx/flx)中分离的脊髓小胶质细胞显示出YO-PRO摄取显著受损(图21、22),但具有正常的P2X7R阳离子通道活性(图23)。尽管这些突变小鼠对吗啡保持正常的抗伤害性反应(图24、25),但脊髓小胶质细胞对吗啡的反应性减弱(图26、27),并且当用纳洛酮激发时,它们显示出相比于表达完整的Panx1通道的吗啡处理的小鼠(同窝的注射载体的Cx3cr1-cre::Panx1flx/flx小鼠)具有显著更少的戒断行为(图28)。
鉴于中枢和外周CX3CR1表达群体的细胞更新率不同(Parkhurst等,2013),另一组小鼠在他莫昔芬处理后给予30天的等待期,以允许在开始吗啡处理之前重建外周CX3CR1表达细胞。因此,这些小鼠仅小胶质细胞中缺乏Panx1。该组小鼠中吗啡戒断的减少与他莫昔芬处理后7天再用吗啡处理的小鼠相当(图29),表明吗啡戒断需要特异性地在小胶质细胞中表达Panx1。作为另一种对照,将他莫昔芬施用至不具有可诱导的Cre重组酶的Panx1loxp /loxp小鼠,并且它们的吗啡戒断反应与表达Panx1的小鼠显示的反应无法区分(图30)。因此,他莫昔芬本身不影响吗啡戒断。为了进一步研究对小胶质细胞Panx1的需求,评估了鞘内10panx(10微克)处理对Panx1缺陷型与表达Panx1的小鼠中纳洛酮催促吗啡戒断的影响。理由是,如果10panx的作用是通过阻断小胶质细胞的Panx1活性而介导的,那么在没有小胶质细胞Panx1的情况下这些作用就会丧失。与用大鼠收集的数据一致,在纳洛酮激发之前的鞘内10panx处理显著地减弱了表达Panx1的小鼠中的吗啡戒断(图31)。相比之下,在缺乏小胶质细胞Panx1且吗啡戒断行为受抑制的小鼠中,10panx没有进一步减少戒断(图31)。10panx效应的丧失以及Panx1缺陷型小鼠戒断的改善,关键地涉及到小胶质细胞Panx1在吗啡戒断中的作用。
为了研究Panx1介导的戒断的基础机制,测量c-Fos表达并表明纳洛酮催促的戒断增加了表达Panx1的小鼠脊髓背角内c-Fos阳性神经元的数量,这种增加在缺乏小胶质细胞Panx1的小鼠中受到抑制(图32、33)。从表达Panx1或小胶质细胞Panx1缺陷的接受了5天盐水或吗啡注射的成年小鼠中制备具有完整背根的整个腰部脊髓制备物,用于直接评估神经元功能。记录脊髓背角椎板I/II的突触后场电位(fPSPs),并注意到应用纳洛酮(10μM)浴产生了缓慢上升的突触促进作用,在吗啡而不是盐水处理的、表达Panx1的小鼠中持续至少60分钟(图34、36)。相反,在吗啡处理的Panx1缺陷小鼠中没有发生对纳洛酮的这种反应(图35、36)。在这些突变小鼠中缺乏突触促进不是由于脊柱突触促进造成的一般缺陷,因为低频(2Hz)电刺激背根产生了fPSPs的强烈且持久的增加(图37、38)。这些数据表明吗啡诱导脊髓背角的可塑性,这可能表现为纳洛酮诱导的戒断时的长期突触促进作用。这种突触促进看上去需要以类似于吗啡戒断的方式激活小胶质细胞的Panx1。
由于ATP释放是Panx1激活的关键结果,因此产生了一个问题,即Panx1介导的ATP释放是否在戒断期间发生。为了测试这一点,将纳洛酮(10μM)浴-施用到从表达Panx1和Pan-1缺乏的用盐水或吗啡处理5天的小鼠中分离的/脊髓切片。测量脊髓超滤液中ATP的量,进而发现吗啡处理的与盐水处理的Panx1表达小鼠相比,对纳洛酮作响应的ATP水平显著更高。在由Panx1缺陷小鼠制备的切片中未观察到这种纳洛酮诱导的作用(图39)。为了分别测试ATP是否从小胶质细胞释放,将纳洛酮应用于培养的小胶质细胞并测量小胶质细胞上清液中ATP的量。纳洛酮引起ATP的释放,其被10panx所阻断(图40)。
为了直接测试ATP是否有助于吗啡戒断,给显示出减毒的吗啡戒断行为的Panx1缺陷小鼠鞘内施用ATPγS。在这些突变小鼠中,局部递送ATP类似物(100μM)连同进行纳洛酮激发,恢复了一系列戒断行为;当将ATPγS施用于盐水处理的Panx1缺陷小鼠时,未观察到这些行为(图41)。有理由认为,如果ATP是吗啡戒断的关键基质,那么改变脊髓内源性ATP水平可能会影响戒断行为。通过鞘内注射ATP降解酶腺苷三磷酸双磷酸酶(10单位),在吗啡依赖性Panx1表达小鼠中测试了这种可能性,其产生惊人的戒断减少(图42)。相反,通过鞘内施用外-ATP酶抑制剂ARL67156(10纳摩尔)来抑制ATP分解,加剧了吗啡戒断(图42)。因此,结论是ATP是吗啡戒断的关键底物。
在确定Panx1关键地参与吗啡戒断后,对两种临床批准的广谱Panx1抑制剂——抗痛风药物丙磺舒,和抗疟疾药物甲氟喹进行了测试,以评估它们对吗啡戒断的影响。在吗啡依赖性大鼠中,在纳洛酮激发前1小时全身施用丙磺舒(50毫克/千克)或甲氟喹(45毫克/千克)显著地改善了吗啡戒断(图43)。这些化合物在吗啡处理的培养的小胶质细胞中还阻断了纳洛酮对Panx1活化的增强作用并抑制ATP释放(图44、45、46、47、48)。丙磺舒和甲氟喹对吗啡戒断的强效作用开启了这些和其他临床可用的广谱Panx1抑制剂可能转化为鸦片制剂戒断治疗的可能性。
总之,戒断是依赖个体停止使用鸦片制剂的主要制止因素。本申请公开了脊髓小胶质细胞中的Panx1活化是吗啡戒断的细胞和行为推论的关键基础。本申请公开了Panx1活化是小胶质细胞在纳洛酮诱导的戒断期间揭示脊髓L1/II神经元中的长期突触促进的基本机制。本申请公开了ATP作为吗啡戒断所需的关键的小胶质细胞-神经元底物从Panx1释放。尽管脊髓背角中的ATP可以来自各种来源,包括初级感觉末梢、神经元或星形胶质细胞,但我们的结果显示小胶质细胞是吗啡戒断的关键ATP来源。对于治疗开发来说特别重要的是,本申请公开了阻断Panx1可有效地减轻吗啡戒断而不影响镇痛。因此,靶向Panx1通道提供了一种临床策略,用于缓解戒断症状而不影响吗啡镇痛。
Claims (9)
1.丙磺舒在制备用于治疗或调节受试者的阿片类戒断多种症状的药物中的用途,其中所述多种症状包括跳跃、牙齿颤动、湿狗摇动、摇头、梳理行为、异常性疼痛、毛发直立、流涎、射精、颤抖/抽搐和体重减轻中的两种或更多种。
2.根据权利要求1所述的用途,其中所述药物用于局部施用。
3.根据权利要求1所述的用途,其中所述药物被配制为洗剂、乳膏、凝胶和粘性液体中的一种。
4.根据权利要求2或3所述的用途,其中所述药物还包含皮肤渗透增强剂、润肤剂、乳化剂、水混溶性溶剂、醇,以及它们的混合物中的一种或多种。
5.根据权利要求4所述的用途,其中所述皮肤渗透增强剂是非阳离子皮肤渗透增强剂。
6.根据权利要求1所述的用途,其中所述药物用于用透皮贴剂施用。
7.根据权利要求1所述的用途,其中所述药物用于通过口服剂量施用。
8.根据权利要求1所述的用途,其中所述药物用于通过注射施用。
9.根据权利要求8所述的用途,其中施用是通过皮下注射进行。
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