CN1662231A - 包括应激相关障碍在内的功能性躯体障碍的预防与治疗 - Google Patents
包括应激相关障碍在内的功能性躯体障碍的预防与治疗 Download PDFInfo
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Abstract
本发明公开了一种对处于压力下的个体通过给药有效剂量的双重血清素/去甲肾上腺素再摄取抑制剂来预防或治疗应激相关障碍的方法。也可对有危险患应激相关障碍的人施用血清素/去甲肾上腺素/多巴胺三重单胺再摄取抑制剂。在一优选实施方案中,化合物是米那普仑,进行预防性给药以有效剂量给药以延迟或防止危险患者的应激相关障碍。
Description
本发明要求由Jay D.Kranzler和Srinivas G.Rao于2002年4月24日提交的名为“功能性躯体障碍的治疗方法”的英国专利U.S.S.N.60/375,068的优先权以及于2003年4月18日提交的名为“压力相关性疾病的预防与治疗”英国专利的优先权利。
发明领域
本发明涉及到一种防范或治疗包括应激相关障碍(SRD)在内的功能性躯体性疾病(FSD)的方法。在一特别方面,本发明涉及到利用具有NMDA(N-甲基-D-氨基天冬氨酸)拮抗活性的血清素和降肾上腺素双重再摄取抑制剂的治疗或预防方法。另一方面,本发明涉及到在治疗患有一种或几种功能性躯体性疾病(FSD)症状的同时治疗功能性躯体性疾病(FSD)的至少一种躯体症状和一种中枢神经系统症状(CNS)的方法。在一优选实施方案中,本发明涉及到了利用血清素/降肾上腺素双重再摄取抑制剂预防或治疗压力相关性疾病(SRD的方法)。
发明背景
百分之七十五到九十拜访医生次数归因于应激相关障碍(SRD)。压力可以影响对于疾病的发作或易感性。即便存在另一潜在的病理生理,它还是可以影响疾病的病理生理学演进和进程。由于压力,从现有疾病的康复可能也会延迟。
应激原是可以破坏身体稳定,血压和其它功能的事件或其它因素。因为人具有复杂的大脑和思考过程,预料应激原破坏的想法也是一应激原。身体通过压力反应响应应激原,这可以改变各种分泌以重建稳定。压力反应可由受伤,饥饿,热,冷或化学接触而激发。压力反应在短期紧急状况下很有用,因为压力反应可以使能量和血压增加,同时暂时限制如繁殖,生长和消化不太重要的功能。但若压力反应是通过慢性激活的话,就可导致疾病发生。例子有抑郁,溃疡,肌纤维痛,慢性疲劳综合症,肠道易激综合征以及其它生理功能紊乱。
无以计数的生理过程在响应压力时改变,其中发生改变的生理过程有皮质(甾)醇,促肾上腺皮质激素,儿茶酚胺和血清素水平。这些水平当急性应激原移除后恢复到基线值(McEwen NEngJMed 1998 338(3):171-179)。这些压力生化标记依次导致健康状况不佳及生理失调,因而压力在身体和精神健康方面发挥了主导作用。
应激相关障碍(SRD)涵盖了很宽泛类别的因个人环境压力所导致的身体障碍,例如高血压,心脏病,头痛,大肠炎,肠道易激综合征,颞下颌关节紊乱综合症,癌症,胃溃疡,失眠,皮肤病和哮喘。压力亦可使其它病况恶化,如表征为暴力或好逗倾向多发性硬化症,关节炎,疱疹,神疾病,药物滥用和精神障碍。压力特别助长了功能性躯体性疾病,情感性障碍和重度抑郁症。慢性疲劳综合症(CFS),纤维肌痛症(FMS),海湾综合症,焦虑和创伤后应激障碍(PTSD)也包括在内。
关于应激相关障碍(SRD)机制的流行理论之一聚焦于下视丘-脑垂腺轴障碍。现存多种神经内分泌异常,如慢性疲劳综合症,纤维肌痛症和抑郁症异常已在应激相关障碍中鉴别出大多数异常与中枢肾上腺皮质激素释放激素低水平相一致,这致使周围儿茶酚胺和肾上腺皮质激素发生变化以及压力反应钝化。慢性疲劳综合症(CFS)病人中,存在下视丘-脑垂腺(HPA)轴钝化现象,包括24小时游离皮质(甾)醇分泌低水平,增强肾上腺皮质对促肾上腺皮质激素(ACTH)敏感性以及削弱ACTH对CRH的反应。这些异常与三级(下丘脑)肾上腺不足相一致(STERNBERG JRHEUMATOL 1993 20:418-421;Beam et al BiolPsychiatry 1995 37:245-252)。在纤维肌痛症(FMS)中,已观察到肾上腺的低反应性伴由皮质(甾)醇下降,放大垂体对CRH的反应表明初级肾上腺不足。类似的异常表明HPA钝化已经在许多并不常见的慢性疾病中有记述,如精神抑郁症或情感性障碍,也参与了知之甚少的障碍如海湾综合症(Gold ET AL NENG JMED 1988 319:348-353;MEANEY ET ALANN N YACAD SCI 1993 697:70-85;VANDERPOOL ET AL JCLIN ENDOCRINOL METABL 199172:1382-1387)。破坏正常锻炼或睡眠型态应激原可能助长了内分泌失衡,导致进一步的睡眠和锻炼困扰。因而形成正向反馈循环,其中疲劳和缺乏锻炼科导致更大压力,因而引起早期SRD并现存疾病恶化到更严重的水平。
在SRD明显化和成为严重健康问题后,有许多针对SRD的疗法。这就需要有效的预防疗法来预防正向反馈循环启动和SRD形成。
可作为例证的SRD是功能性躯体障碍(FSD),它的特征更在于症状,受疾病折磨和不能而非持续表现出的组织异常(Barsky et al Ann Intern Med 1999;130:910-921)。据估计,FSD影响高达20%的人群。功能性躯体障碍(FSD)的例子包括偏头痛和紧张性头痛(MTH),肠道易激综合征(IBS),经前焦躁症(PMDD),颞下颌障碍症(TMD),多发性化学敏感(MCS)和间质性膀胱炎(IC)。
所有这些FSD所共同具备的症状,不同程度上包括疼痛,劳累和认知和/或记忆困难(Aaron et al Ann Intern Med 2001;134:868-881),与普通人群相比,所有症状都伴有高普遍性的失眠障碍(Katon et al Ann Intern Med 2001;134:917-925)。FSD中普遍存在的疼痛症候学,被认为归因于由广泛性躯体感知提高和/或内脏感觉刺激。
FSD出现的一特别障碍是对障碍的病因和影响其的生物,环境和其它因素并不充分理解。假定所感知到的FSD不同表现不相关,通常利用不同医学学科对其加以治疗,有时会用相同药物治疗,有时则用不同药物处理这些不同的表现与适应症。目前所施用的治疗FSD各种征象的一些药物包括:镇痛剂,催眠剂,免疫抑制剂,其它各种处方药以及一系列非处方药。在治疗此类障碍的各种征象时,未证实任何一种药理制剂或制剂组合有效。因缺乏将FSD作为单一性疾病的普遍的共识,缺乏有效的FSD治疗方法,函需研发出有效的治疗方法。因有共同的症状分类,认为功能性躯体障碍与之相关。但其显现出不同的主要症状。
历史上抗抑郁剂(AD)曾在治疗多种FSD中起到了突出的作用。实际上,许多FSD对于用多种类的AD治疗的反应被部分或全部用于揭示FSD的共同病因,它是以“情感类型疾病”形式,症状本身和伴随的精神病理学享有共同的生理病理特征。但尽管不同类别的抗抑郁剂对其它“情感类型疾病”有深刻的影响。在FSD治疗中,特别对选择性血清素再摄取抑制剂(SSRI)类药物而言,AD的作用有限,而且,尚无对此提出的共有病因的本质和细节的描述,未指出或甚至暗示出在情感类型疾病的症状之间有因果关系。在下列出版物中,对这些观点进行了特别讨论。(Gruber et al Psychiatric Clinics of N.America 1996;19:351-369,Hudson and Pope,Amer J Psychiatry 1990;147:552-564,and in Hudson et AL.,Journal of Rheumatology 1989;16:15-22)。多变量表明1)许多因素助长了症状演进;2)没有任何单因子对疾病演进是必要的;以及3)这些因素以不同方式组合互作。例如,心理因素如压力或躯体化生理因素可明显的使FSD症状恶化。
在另一解释FSD共病的方法中,当这些解释“偏袒”选用生物学而非心理学中作为其它伴随症状的主要原因,意味着要采用证实性假设。这些模型可划分为以FSD生理症象为主和以精神困扰为主。但这些范例的临床预测与临床的经验观测结果并不完全一致。例如,已证实抗抑郁剂在几乎所有病例中的FSD情绪部分中有效;但对于症状的疼痛部分的功效则很不一致。统计分析支持了即便在精神痛苦水平受控时候,不同FSD仍是相互独立的。可特别参见Clauw Med Hypotheses 1995;44:369-378;Mayer Gut 2000;47:861-869;Barsky 1999;op cit;Robbins et al J Nerv Mental Dis 1997;185:606-615;and Whorwell et al Gut 1986;27:37-40。
因没有从这些解释产生任何待验证的假设,所有提出的模型存在的问题是它们没有为病人选择疗法提供方向,也没有为新药物开发提供任何方向。现在仍然存在着为治疗受FSD困扰的病人的研发有效疗法的重大需求。
本发明的目的之一是提供一种有效的疗法,用来治疗于这些迹象恶化为严重SRD之前在急性压力下表现出轻微压力迹象的个体。
本发明的进一步目的是提供鉴别和利用一种化合物治疗易患SRD的个体以防范SRD症象的方法。
本发明的进一步目的在于提供在SRD出现直到应激原去除后,利用一种药物组合物治疗急性压力下个体的方法。
发明概述
本发明开发出了预防或治疗应激相关障碍的方法,如功能性躯体障碍(FSD)和/或与其相关的症状。方法通常包括同时治疗FSD的至少一种躯体症状和一种中枢神经系统(CNS)症状。在一优选实施方案中,施用了一特型双重血清素/去甲肾上腺素再摄取抑制剂(″DRI″)复合物或其药学可接受盐。最优选的DRI复合物是非三环类SNRIS,其对血清素再摄取抑制比去甲肾上腺素再摄取抑制程度要深;以及NSRIS,其中非去甲肾上腺素再摄取抑制比血清素抑制化合物是要程度要深。最优选的化合物是米那普仑(milnacipran)或一种生物等效物或其药学可接受盐。其它优选的化合物是度洛西汀(duloxetine)和文拉法新(venlfaxine)或其药学可接受盐。在另一具体实施方案中,施用了治疗有效剂量的一特型非三环三重再摄取抑制剂(″DRI″)复合物或其药学可接受盐。
TRI复合物特征在于其可以阻断再摄取(从而增加中枢浓度)三种主要脑单胺:血清素,去甲肾上腺素和多巴胺。
发明详述
缩写
CFS慢性疲劳综合症
FMS纤维肌痛综合征
PTSD创伤后应激障碍
SRD应激相关障碍
FSD功能性躯体障碍
5-HT血清素
NE去甲肾上腺素
NMDA N-甲基-D-天门冬氨酸受体
NSAIDs非甾体类抗炎药物
SSRIs选择性血清素再摄取抑制剂
TCAs三环抗抑郁剂
SNRIs双重血清素/去甲肾上腺素再摄取抑制剂
5-HT>NE is implied。
意味5-HT>NE
NSRI NE>5-HT SNRI的替代缩写
DA多巴胺
TRI可阻断5-HT,NE和DA再摄取的化合物。
DRI一类可阻断5-HT和NE再摄取的化合物。这类化合物可进一步再划分为SNRI和NSRI亚类。
定义
术语“双重血清素/去甲肾上腺素再摄取抑制剂化合物”(此处也指DRI化合物)是指已熟知的可抑制血清素和去甲肾上腺素再摄取的抗忧郁药化合物。常规的DRI化合物包括,但不限于文拉法新(venlfaxine),度洛西汀(duloxetine)和米那普仑(milnacipran)。
术语″NE>5-HT SNRI″或″NSRI″是指可比抑制再摄取血清素更大程度抑制去甲肾上腺素再摄取的一特殊亚类的DRI化合物;此亚类在本发明方法的一特别实施方案和试剂盒中很有用,此处将更加详细的加以描述。
术语SNRI是指可比抑制血清素再摄取更大程度抑制去甲肾上腺再摄取特定DRI化合物。
术语TRI是指可抑制血清素,去甲肾上腺素和多巴胺再摄取的具有抗抑郁,厌食和抗帕金森性能的一类化合物。
术语偏头痛和紧张性头痛是指可导致头痛的障碍。偏头痛通常为单向悸动性头痛,伴有下列部分或全部症状-恶心,呕吐,畏光(不喜光),害怕声音(不喜喧闹)。疾病发作持续平均4-72小时,程度为中度至重度,并因运动而加剧。紧张性头痛是非特异性头痛,不是血管性或偏头性头痛且与器官疾病无关。此头痛是由颈和头皮后部肌肉拉紧造成的。术语非典型性面痛是指涵盖很宽泛组类的面部疼痛问题的症状,包括在面部一侧,通常在三叉神经区域的发热,疼痛或抽筋,可延及上脖颈和头皮后部,持续几乎无间歇发作。
术语非心胸痛是指不是由心脏引发地胸痛。最常见地非心胸痛出现于食道,包括胃食管反流病(GERD)和食道痉孪。
术语肠道易激综合征是指干扰大肠(colon)正常功能的疾病,该病特征是有一组症状-腹绞痛,肿胀,便秘和腹泻。肠道易激综合征(IBS)可导致大量地不适和痛苦。它并不持久危害肠类,但可使某些人丧失能力。
术语经前烦躁症是指在经期前与女人周期相关地系列的虚弱症状,也是重度精神障碍的精神病术语。经前烦躁症(PMDD)太严重了,可使女性的日常活动完全得到中断。颞下颌障碍症(TMD)不单指一种障碍,而是一组条件,通常疼痛,影响到颌关节(颞下颌关节,或TMJ)以及控制咀嚼的肌肉。这些疾病可划分为三类:面肌疼痛,退行性骨关节病,关节内紊乱。
术语多重化学敏感症是指在接触对大多数人来说非毒性或过敏性的家居或环境物品时,个体报告有多发性抑郁症的障碍。
术语间质性膀胱炎是指一种慢性盆腔疼痛症,是可导致复发性不适或膀胱和盆骨区域疼痛的情况。
症状包括尿急,尿频,或这些症状的组合。疼痛强度当膀胱充满尿液或清空时发生变化。
术语慢性下腰痛是指腰部区域的疼痛持续超过六个月,尽管疼痛可能时不连续的。
I应激相关障碍
有多种已知疾病由压力引发或因压力而恶化。这些疾病包括成瘾性疾病如药物滥用,厌食,易饿病,肥胖,烟瘾和体重成瘾;焦虑疾病如开放恐惧症,焦虑症,强迫性神经症,恐慌发作,表现焦虑,恐怖症和创伤后应激障碍;自免疫疾病如过敏,关节炎,纤维肌痛,纤维肌瘤,狼疮,多发性硬化症,风湿性关节炎,舍格伦综合征(Sjogren’ssyndrome)和白癫风。癌症如骨癌,脑癌,乳房癌,子宫颈癌,大肠癌,何杰金病(Hodgkin’sdisease),白血病,肝癌,肺癌,淋巴瘤,多发性骨髓瘤,卵巢癌,胰脏癌和前列腺癌;心血管疾病如心律不整,动脉硬化,汉堡病(Burger’s disease),原发性高血压,心室纤维颤动,二尖瓣脱垂,心悸,外周血管疾病,雷诺氏病(Raynaud’s disease),中风,心搏过速,心律异常疾病预激综合征(WOLFF-PARKINSON-WHITE Syndrome);进展性障碍如注意力缺陷症,专注问题,行为障碍症,诵读障碍,运动机能亢进(hyperkinesis),语言和讲话障碍和学习能力障碍。
本发明治疗方法的最相关的应激相关障碍包括功能性躯体障碍(FSDs),焦虑症和重度忧郁症。
a.功能性躯体障碍
功能性躯体障碍(FSD)包括,无限制:慢性疲劳综合症(CFS),纤维肌痛综合征(FMS),偏头痛和紧张性头痛(MTH),肠道易激综合征(IBS),非典型性面痛(AFP),经前焦躁症(PMDD),颞下颌障碍症(TMD),非心胸痛(NCCP),多发性化学敏感(MCS),间质性膀胱炎(IC),慢性盆腔痛(CPP),慢性下腰痛(LBP)集合,特征在于症状,病患折磨和无力甚于组织异常。FSD的共同症状,不同程度上包括疼痛,疲劳和认知和/或记忆障碍(Aaron et al Ann Intern Med 2001;134:868-881),且与普通人群相比,都与失眠的高度普遍性相关(Aaron ET AL ARCH INTERN MED 2000;160:221-227)和精神病困扰(Katon ET AL ANN INTERN MED 2001;134:917-925)。FSD中普遍的疼痛的分类学症状被认为是广泛性的躯体和/或内脏感官刺激的感知强化所引起的。患有FSD的病人常以痛超敏(无害刺激引起的疼痛)和痛过敏(对疼痛刺激物增强的敏感性)表现出疼痛感知异常。
据估计大约有20-40%患有FSD的个体具有可鉴别的当前情绪障碍,如诊断时的沮丧,焦虑。据报道终生的抑郁可高达70%(Boissevain,and MCain Pain.191:227-38;Boissevain and MCain,Pain.1991;45:239-48;Hudson et al.Am JPsychiatry 1985;142:441-6)191:227-38;Boissevain and MCain,Pain.1991;45:239-48;HudsonET AL.
FSD出现的一特别障碍是对障碍的病因和影响其的生物,环境和其它因素并不充分理解。假定所感知到的FSD不同表现不相关,通常利用不同医学学科对其加以治疗,有时会用相同药物治疗,有时则用不同药物处理这些不同的表现与适应症。当前所施用的治疗FSD各种症象的一些药物包括,但不限制于镇痛剂,催眠剂,免疫抑制剂,其它各种处方药以及一系列非处方药。
一特别的FSD是以1990-1991波斯湾战争烙饼命名的海湾综合症。病因并不很清楚,但综合症的特征是出现诸如慢性疲劳,肌肉和关节痛,头痛,皮疹,注意力和记忆力问题,呼吸问题,睡眠困扰,肠胃障碍和抑郁。基于选择的表现症状鉴别出两种类型的海湾综合症。综合症1(认知受损)特征是抑郁和注意力障碍。此症状通常发现于穿着含有杀虫剂的防蚤圈的老兵上。综合症2(神志不清-共济失调)是最独特的形式,特征是思维与推理受损,头昏,平衡和协调缺陷。此症状通常发现于声称接触神经毒气的海湾战争老兵上。数据表明此类型的老兵大脑受损范围最大(Haley et AL.NEURORADIOLOGY 2000 215:807-817)。
尽管在FSD病人中施用了很宽范围的药物,没有任何单独一种药理制剂或制剂组合表明在治疗这些障碍的各种症象时有效。因缺乏将FSD作为单一性障碍的普遍共识,缺乏有效的FSD治疗方法,函需研发出有效的治疗方法。
b.焦虑症
焦虑症是美国最常见的一组精神疾病。每年有超过一千九百万美国成人受此衰弱疾病困扰。
孩童和青少年也可发生焦虑症。焦虑症是严重的影响将近一千九百万美国成人的严重医学疾病。这些疾病使得人们生活中充斥了焦虑与恐惧。与相对温和的焦虑不同,它是由压力事情引发的短期焦虑,商业陈述或初次约会。焦虑症是慢性的,无情的,如不治疗的话将逐渐恶化。鉴别出来的四种主要类型的焦虑症:惊恐障碍,强迫性神经症,创伤后应激障碍,广泛性焦虑和恐怖症(包括社交恐怖症,也称作社交焦虑障碍)。每种焦虑症有其自己独特的特征,但其与过度,非理性恐惧和担心常提到的主题联系在一起。通常焦虑症伴随有抑郁,进食障碍,药物滥用,或另外的焦虑症。
焦虑症也可与癌症或心脏病共存。在此种情况下,需要对伴随的疾病加以治疗。在开始治疗前,很有必要进行一全面的医学检查以排除其它可能的导致症状出现的原因。
i)恐慌症特征是经常无预兆的受剧烈恐惧重复侵袭。身体上症状包括胸痛,心悸,气短,头昏,腹窘迫,感觉不现实和怕死。
ii)强迫性神经症特征是有重复,多余的想法;似乎无法停止或控制的想法或强迫性行为。
iii)创伤后压力症特征是在经历或目睹创伤性事件如强奸或其它犯罪袭击,战争,虐待儿童,自然或人为灾害或飞机失事后持续的症状。通常表现噩梦,回想,精神麻木,抑郁和感到愤怒,易怒或心烦意乱,易受吓。患者的家庭成员亦会演化出这种疾病。创伤后应激障碍(PTSD)是一在恐怖时间后演化出的使人衰弱的情况。引发PTSD的事件可以是威胁个人生命或与他/她关系亲密的人或是目睹的某些事情。
无论此问题来源如何,患PTSD的人重复性的以噩梦和白天烦忧的回忆形式再现创伤,白天烦忧的回忆的形式。他们也可能经历其它的睡眠问题,感觉失落或麻木,或易受惊吓。他们可能对他们曾经感兴趣的事情失去兴趣。他们可能感到烦躁易怒,比以往更好斗,或者暴力。可使他们回忆创伤的事情可能使其非常痛苦,这可以使得他们避免去某些地点或使其回忆的场合。创伤事件的周年通常非常难受。
PTSD影响到了520万美国成年人。妇女比男人更易于进展为PTSD。PTSD可以在任何年龄发生,孩童时期也包含在内。有一些证据表明对PTSD的易感性可蔓延至全家。此病症伴随有抑郁,药物滥用,或一种或多种其它焦虑症。更严重的情况下,病人可能出现工作或社交出现障碍。
iV)广泛性焦虑症特征是有加剧忧虑想法,对日常生活事情和活动的紧张可持续达6个月。即便没有任何理由去那么想,通往最坏处想;伴随有身体症状,如疲劳,发抖,肌肉紧张,头痛,或呕吐。
V)恐怖症可划分为两个主要类型,社交恐惧和特殊环境恐怖恐惧。有社交恐惧的人在社交场合有无法自控的害怕指摘,窘迫,或感到耻辱,这可使其避免参与到潜在愉悦和有意义的活动。有特殊环境恐怖的人会体验到极端的无力控制和无理性的对很少或没有实际危险的事情的恐惧;恐惧可以导致避开物体或场合并可使人不必要的对他们自己的生活施加限制。
c.重度忧郁症
重度忧郁症是指一类这样的症状,特征是情感消极以及重复性的抑郁发作,没有任何可满足狂燥的标准的情绪高涨或过分活跃的单独发作历史。已经鉴别出多种重度忧郁症,包括有非典型特性,精神病学成分的症状等。间歇性抑郁症的发作年龄及其严重程度,持续时间和频率均是高变因素。平均的发作年龄是在20多岁晚期,但症状可以发生在任何年龄。重度忧郁症的症状通常进展从几天到几周。前驱症状包括广泛性焦虑,恐慌发作,恐惧症或抑郁症状,可在间歇发作前几个月发生。个体间歇发作持续3到12个月,但不易复发。在间歇期间通常康复完全,但许多病人可能主要在老年会进展为持久的抑郁。任何严重度的个体发作均可因紧迫的生活事件急剧降低;在多种文化中,在女性中个人发作和持久性抑郁是男性的两倍。此疾病其中与涉及到遗传成分,普遍上,患病的生物学上一级亲属是大众患病的1.5到3倍。抑郁性的发作通常症状包括专注和注意力下降;自尊心和自信心下降;有内疚和无价值想法;有自我伤害或自杀的想法或行为;睡眠障碍;以及食欲下降。重度抑郁发作常在社会心理应激原后发生,特别是所爱的人的死亡,离婚,分娩或重要关系的终结。低落的情绪每天变化不大,通常不对环境反应迟钝,但也会随着时光流逝表现出特征性的每日变化。至于躁狂发作,临床症象表现出明显个体变异,在青少年中普遍表现出非典型症象。一些情况下,焦虑,痛苦,有时很明显的躁动不安,抑郁和情绪变化也可被额外的特征如易怒性,过度饮用酒精,夸张行为以及现有病态性恐惧或强迫症状或臆想病所掩盖。不考虑到抑郁发作严重程度,持续达两周通常需要去做诊断,但若症状严重且突然发作,较短的时间也是合理的。多种亚型对不同类的抗抑郁剂的反应不同。例如,已经表明具有非典型抑郁情形对单胺氧化酶抑制剂(MAO-1)反应最好,比三环类抗抑郁剂好。
II.下视丘-脑垂腺轴功能障碍
SRD演化已经暗示出下视丘-脑垂腺轴的参与(Clauw and Chrousos,Neuroimmunomod1997 4:134-153)作为应激原之间的链接,例如疼痛以及个人的内分泌,自律和行为反应。经典上认为HPA是通过生成可介导生理变化以保持动态平衡的化学信使从而对环境变化作出反应的程序化系统(Chrousos(1998)AnnNYAcadSci 851:311-351)。但最近的证据使此简单模型复杂化,它提出遗传影响,生命早期环境因子以及接触慢性压力可持久影响HPA,成为疾病进展的诱导条件。但大多数工作是在理解了这些变化对情感障碍的病理生理学作出的贡献的境况下所完成的(Heim and Nemeroff 1999),认为同样的机制在FSD中起作用(Neeck and Crofford(2000)Rheum Dis Clin North Am 26(4):989-1002。
HPA级联的主要媒介是促肾上腺皮质激素释放因子(CRH),它是室旁下丘脑里所生成的响应物理或生理压力的一种神经肽。CRH依次刺激促肾上腺皮质激素(ACTH)从垂体前叶细胞的释放,其可促进肾上腺皮质激素从肾上腺的释放以引发对所观察到的危险的适应性反应,例如血液葡萄糖水平升高(Neeck and Crofford(2000)Rheum Dis Clin NorthAm 26(4):989-1002)。CRH还能作为神经递质对生长素和促甲状腺激素(TSH)施加二级抑制作用,增加生长激素抑制素从下丘脑和皮层神经元的分泌(Peterfreund and Vale(1983)Endocrinology 112(4):1275-8)以及下丘脑LHRH的释放(Frias,Puertas etal.(1997)NEUROCHEM Res 22(2):171-4)。同时激活HPA轴,生物对压力采取由自律神经系统介导的“对抗或逃跑”反应,可导致如心动过速或高血压类的生理变化。
III.危险因子
有许多可使个人易于患SRD的危险因子。这些因子可以在进展为严重压力相关症状之前鉴别出候选者进行应激相关障碍的预防性治疗。以前利用危险因子来鉴别易于患压力相关性焦虑症,如PTSD,危险因子是相关的。这包括:(a)先前的外伤,(b)先前生理调节(c)家庭精神病理学史,(d)创伤时感觉到的生命威胁,(e)外伤后社会援助,(F)周围创伤情绪反应,以及(g)周围创伤离解。感知到的应激原不可逃避或不可避免或伴随有缺乏可预见性或支持,诱发最强烈的不良生物学后果。
女性很明显是主要危险因素,许多应激相关障碍在女性中比在男性中更盛行。例子有CFS,FMS,PTSD和中毒抑郁症,这疾病在女性中比在男性中更明显。
应激原所体验的环境非常重要,特征为失控,无助和无可预见性环境接触与有很大可能性导致慢性疾病的急性应激原有关联,在此范畴内,出现了如孩童时代/发育性虐待。以前的研究利用了早先的创伤,如性创伤,普通创伤,违法用药,先存精神疾病(最特别是焦虑症和违法用药症)。因神经系统的可塑性,生命早期应激原可对随后动物中对压力的生物学响应有持久的影响。可塑性可能归因于神经元的数目,通路数目和/或增强或减弱的基因表达,这可导致明确系统功能的持久的变化。这可以解释为什么个体进展为FMS,CFS,躯体形式障碍,IBS,和相似障碍笔表现出比期待要高的孩提时期身体和性虐待关联度(Walling et al Obstet Gynecol 1994 84:200-206;Spaccarelli Psychol Bull 1994116:340-362;Bendixen et AL CHILD ABUSE NEGL 1994 18:837-847)。
可能存在遗传危险因子使个体易于患急性应激原慢性后遗症。很有可能演化此系列遗传障碍的易患病性的真正归因于压力反应中的遗传差异。人压力反应的基线异常如下丘脑-垂体肾上腺轴的低或高活性,或自律神经系统可能使人易于患慢性SRD。可破坏正常锻炼或睡眠方式的应激原可以使个人置于进化为慢性SRD高度危险下。
临床前发现有力表明CRH在特定焦虑症病理生理学的作用,可能是影响中枢去甲肾上腺素系统(Arborelius ET AL JENDOCRINOL 1999 160(1):1-12)。已经表明患抑郁症的病人去甲肾上腺素起了作用,它受到压力的影响(Leonard JPSYCHIATRY NEUROSCI2001 26 Suppl:S11-6)。以前没有利用去甲肾上腺素/血清素混合制剂的报道和利用急性应激原以防范这些后遗症。这种化合物将增强中枢去甲肾上腺素和血清素系统,补偿个人易于患这些后遗症的低活性,直到急性疼痛,疲劳,压力消失,他们可以开始睡眠,又可正常锻炼。
IV.组分
在一优选实施方案中,预防性的给药单胺再摄取抑制剂来预防SRD发作。在一更优选实施方案中,在急性应激原后,给药NSRI直至急性疼痛,疲劳和抑郁消失。在最优选实施方案中,NSRI是米那普仑(milnacipran)。
本化合物优选以有效剂量以预防一种或多种症状的发作,或缓解应激相关障碍的症状。待给药的有效剂量的化合物优选来预防压力相关性疾病进展为或恶化为更严重的状况。
在一实施方案中,可用抑制血清素,去甲肾上腺素和多巴胺再摄取的TRI化合物来预防或治疗患有FSD或具有FSD症状的个体。多巴胺再摄取抑制活性通常包括阻断多巴胺转运体(DAT)以抑制多巴胺再摄取。化合物阻断DAT的能力或增加多巴胺释放的能力可利用几种现有的技术加以确定。例如,GAINETDINOV ET AL.,(1999,Science,283:397-401),描述了一种技术,其中组织层中的细胞外多巴胺浓度可用微透析来测定。为确定化合物阻断DAT的能力或增加多巴胺的释放,多巴胺细胞外浓度可在给药所述化合物前后测量。给药检测的化合物后,统计学上多巴胺水平的显著增加表明所述化合物抑制了多巴胺的再摄取或增加多巴胺的释放。可用多巴胺转运体的抑制浓度(IC)值,如IC50来定量化此化合物阻断DAT的能力。现有技术描述几种技术来测定IC值(例如,参见ROTHMAN ET AL.,2000,SYNAPSE,35:222-227)。在这些方法中有用的化合物通常IC50值范围是0.1nM到600μM。这些化合物特别具有IC50值为从0.1nM到100μM。TRI化合物的一特别实施例是曲美(BTS 54 524;N-[1-[1-(4-氯苯基)环丁基]-3-甲基丁基]-N,N-二甲胺一水盐酸盐)(N-[1-[1-(4-氯苯基)环丁基]-3-甲基丁基]-N,N-二甲胺一水盐酸盐),或其药学上可接受盐。曲美阻断了神经递质多巴胺,去甲肾上腺素和血清素再摄取。曲美的化学结构在现有技术中是公知的。本化合物在美国专利U.S.Patent No.4,939,175和Buckett等人有描述。(Prog.NUERO-PSYCHOPHARMACOL.&BIOL.PSYCHIAT 1988 vol.12:575-584)。
三环抗抑郁剂是众所公认的一类抗抑郁化合物,特征是有一融合的三环核。如此处所描述,这类化合物并不适合于此处利用。通常分类为三环抗抑郁剂,包括丙咪嗪,去甲丙咪嗪(desipramine),氯米帕明(clomipramine),三甲丙咪嗪trimipramine,阿米替林,去甲替林,多塞平和去甲替林。
在一优选实施例中,DRI化合物是NSRI化合物,且表现出对去甲肾上腺素比血清素表现出更大程度的抑制。在一实施例中,NSRI化合物对甲肾上腺素再摄取/血清素再摄取(″NE∶5-HT″)的比率约为2-60∶1。也就是,NSRI化合物对对甲肾上腺素再摄取的抑制是血清素再摄取的抑制的2-60倍。具有NE∶5-HT比例约为10∶1到2∶1的NE>5-HT SNRI化合物认为特别有效。
现有技术已知多种技术来测定特别SNRI的NE∶5-HT。例如,可以通过NE和5-HT再摄取抑制的IC50数据来计算比率。已有报道说对米那普仑来说,去甲肾上腺素再摄取的IC50是100nM,而血清素再摄取抑制的IC50是200nM。参见Moret等人(Neuropharmacology,24(12):1211-1219,1985);Palmier,C,et al.(1989)。因此,米那普仑的基于此数据的NE∶5-HT再摄取抑制比率是2∶1。当然,只要对于去甲肾上腺素和血清素的相同的IC值进行比较,其它IC,如IC25,IC75等等可以利用。取得理想程度的抑制的必要浓度(例如,IC值)可以利用已知的体内或体外技术加以测量。参见Sanchez and Hyttel(Cell Mol Neurobiol 19(4):467-89);Turcotte et al(Neuropsychopharmacology.2001 May;24(5):511-21);Moret et al(Neuropharmacology 1985 DEC;24(12):1211-9.);MORET and BRILEY(NEUROPHARMACOLOGY.1988 Jan;27(1):43-9);Bel and Artigas(Neuropsychopharmacology.1999 Dec;21(6):745-54);Palmier et al(Eur J ClinPharmacol 1989;37(3):235-8).)
此类NSRI化合物的实施例包括米那普仑。另外可资利用的SNRI化合物包括WO95/22521专利公开的氨基环丙烷衍生物;美国专利U.S.Patent No.5,621,142;Shuto等,J.MED.CHEM.,38:2964-2968,1995;Shuto等,J.MED.CHEM.,39:4844-4852,1996;Shuto等,J.Med.Chem.,41:3507-3514,1998;and Shuto等,85:207-213,2001结构上与米那普仑相关而可对去甲肾上腺素再摄取的抑制比对血清素再摄取的抑制更大可以用来实施本发明。
米那普仑及其诊断方法在美国专利U.S.Patent 4,478,836已有描述。关于米那普仑的额外信息可以在Merck参考,第12修订版,6281登录。除非特别指出,此处所用术语“米那普仑”是指对映体纯的米那普仑以及米那普仑对映体混合物。
另一SNRI化合物的特别实施例是洛西汀(duloxetine),或其药学可接受盐。洛西汀通常以盐酸盐形式施用于人和最经常施用是(+)对映体洛西汀的化学结构为本领域熟练技术人员所熟知。洛西汀及其合成方法在美国专利U.S.Patent number 4,956,388中有描述。关于洛西汀的其它信息可以从Merck参考,第12修订版,3518登录
再一SNRI化合物的特别实施例是文拉法辛(venlafaxine),或其药学可接受盐。文拉法辛通常以盐酸盐形式施用于人和最经常施用是(+)对映体。文拉法辛的化学结构为本领域熟练技术人员所熟知。文拉法辛及其合成方法在美国专利U.S.Patent numbers 4,535,186和4,761,501中有描述。关于洛西汀的其它信息可以从Merck参考,第12修订版,10079登录,应该理解此处所用的文拉法辛是指文拉法辛基自由基,其药学可接受盐,外消旋酸盐(或酯)和单个对映体以及外消旋酸盐(或酯)和单个对映体文拉法辛类似物。本领域熟练技术人员将会意识到SNRI化合物如米那普仑可表现出互变现象,构象异构,几何异构和/或光学异构。例如从以上结构图可以清楚看到,米那普仑光学活跃。在文献中已报道有右旋对映体与外消旋混合物相比是其抑制去甲肾上腺素和血清素再摄取活性的两倍左右,左消旋不如右旋对映体有效(参见,E.G.,SPENCER AND WILDE,1998,SUPRA;Viazzo et al.,1996,Tetrahedron Lett.37(26):4519-4522;Deprez etal.,1998,Eur.J.DRUG METAB.PHARMACOKINET.23(2):166-171)。因此,以对映体纯形式施用的米那普仑(例如,纯右旋对映体)或右旋或左旋对映体混合物,如外消旋混合物。分离并提纯米那普仑右旋或左旋对映体及其它SNRI化合物的方法已为人所熟知(例如参见GRARD ET AL.,2000,Electrophoresis 2000 21:3028-3034)。
可以理解的是许多情况下SNRI可代谢产生活性SNRI化合物且所产生的代谢物可资利用。
谷氨酰氨系神经传递在可导致常伴随SRD的超敏性的中枢性敏感化中发挥了重要作用。因此可抑制谷氨酰氨系神经传递的化合物,如NMDA拮抗剂在治疗SRD时特别有用。已有报道米那普仑和其衍生物在NMDA受体上有拮抗特性。(参见Shuto et AL.,1995,J.Med.Chem.,38:2964-2968;Shuto et al.,1996,J Med.Chem.,39:4844-4852;Shuto et al.,1998,J Med.CHEM.,41:3507-3514;and Shuto et al.,2001,JPN.J.Pharmacol.,85:207-213.)。具有NMDA受体拮抗特性的SNRI化合物的IC50约为1nM-100μM。例如,已有报道米那普仑的IC50的值约为6.3μM。米那普仑的NMDA受体拮抗特性和衍生物Shuto等已有描述(Shuto et AL.,1995,J.Med.CHEM.,38:2964-2968;Shuto et al.,1996,J Med.Chem.,39:4844-4852;Shuto et al.,1998,J Med.CHEM.,41:3507-3514;and Shuto ET AL.,2001,JPN.J.PHARMACOL.,85:207-213.)拮抗和拮抗亲和力的测定方法已有公开(Shuto et AL.,1995,J.Med.CHEM.,38:2964-2968;Shuto et AL.,1996,J.Med.CHEM.,39:4844-4852;Shutoet al.,1998,J.Med.CHEM.,41:3507-3514;and Shuto et AL.,2001,JPN.J.PHARMACOL.,85:207-213.)。氨基环丙烷衍生物已有公开(WO95/22521;U.S.Patent No.5,621,142;Shuto et al.,J.Med.Chem.,38:2964-2968,1995;Shuto et al.,J.Med.CHEM.,39:4844-4852,1996;Shuto et al.,J.Med.Chem.,41:3507-3514,1998;and Shuto ET AL.,JPN.J.PHARMACOL.,85:207-213,2001可抑制与5-HT相比更可抑制NE的再摄取且具有NMDA拮抗特性。
SNRI化合物如,米那普仑可在施药时附加入其它活性物质如抗抑郁剂,镇痛剂,肌肉松弛剂,压食剂,抗癫痫药物和镇静催眠药。可与SNRI一起加入的特殊化合物实施例包括但不限于加巴喷丁(neurontin),普加巴林(pregabalin),普拉克索(Pramipexole),左多巴(L-DOPA安非他明(amphetamine),替扎尼定(Tizanidine),可乐亭9clonidine),曲马多(tramadol),吗啡(morphine),三环抗抑郁药(tricyclic antidepressants),可待因(codeine),卡母巴马泽啡(cambamazepine),曲美(Sibutramine),安非他明(amphetamine),安定(valium),查诺顿(Trazodone)及其组合。通常对SRD患者而言,SNRI可在施药时附加入抗抑郁剂,镇痛剂,肌肉松弛剂,压食剂,抗癫痫药物和镇静催眠药。此处所用的辅助施药物意味着同时以相同剂形同时施用此类化合物,以分次剂形的同时施用此类化合物以及分次施用此化合物。例如,米那普仑可以同时与安定(valium)同时给药,其中米那普仑与安定配方于同一种药片中。也可选择将米那普仑和安定置于两个药片中,将米那普仑和安定一起施用。另一种选择是在施用安定后施用米那普仑,或反之亦然。
优选治疗性以有效剂量对SNRI化合物给药以防止一种或多种症状的发作,或缓解应激相关障碍。
化合物的有效给药物剂量优选可防范应激相关障碍进展为或恶化为更严重的情形。SNRI化合物可以治疗性的施用用以取得治疗好处或取得预防好处。治疗益处意味着根除或改善相关的潜在疾病,如根除或改善潜在SRD,和/或根除或改善一种或多种与潜在疾病相关的症状以使病人可报告感觉或状况改善,尽管病人可能还受潜在的疾病困扰。例如,对SRD患者用药物米那普仑不仅当潜在的SRD根除或改善时,也当报告出病人任何一种SRD特别症状减弱,例如,疲劳减弱,睡眠改善,和/或疼痛严重度或持续时间减弱时,病人也可受益。
V.利用方法
为治疗用药,SNRI化合物通常施用于已经诊断并治疗了某一特别症状。
为预防用药,SNRI化合物通常施用于有患SRD风险的病人或报告有一种或多种SRD生理症状的病人,即便还未做SRD诊断。另一选择是可预防性施药以避免潜在疾病的生理症状的发作,特别是当症状周期表现。在后一个实施方案中,至于相关的生理症状而不是潜在迹象,本治疗是预防性。例如,可在睡觉前预防性的施用SNRI化合物以免睡眠障碍与SRD相关联。另一种选择是可在某一特定症状复发或发作之前给药,如疼痛或疲劳。
个体评价
可基于上述的危险因子评价个体,确定是否存在演化为SRD易患病性。若个体确定有明显危险或与应激原剧烈接触,可实施此疗法。在一优选实施方案中,可在任何一种压力相关症状发做前施用此化合物。
可进行生理压力检测以测量在身体不同系统中呈现出压力诱导焦虑度(例如,肌肉,心血管,消化系统,呼吸系统和神经系统)。在技术中通常利用这些压力检测。将检测结果与地方和国家标准进行比较以确定是否个体是否表现出过度的生理焦虑以及他们是否可以从一标准压力刺激中在适当长时间内康复。可以利用生理检测来监控属于危险群体的个人来确定精神和/或压力疾病的社会病因。这些检测为现有技术公知,包括健康相关评价,精神健康评价,个性检测和个性类型评价。
B配制和用药途径
这些化合物或其药学可接受盐可作为药物组分配制,包括其多态变异物。这些组分可以口服,口腔,肠胃外,喷雾吸入,直肠,皮内,透皮或局部施用含有所期待的常规非毒性医学可接受载体,增效剂和载体剂量单位配方形式。局部用药也包括透皮用药如透皮贴或离子电渗疗法装置。此处所用术语肠胃外包括皮下,静脉内,肌肉间或胸骨内注射或灌输技术。优选实施方案中,组分口服给药。
组分的配方有讨论,例如Hoover,John E.,REMINGTON’S PHARMACEUTICALSCIENCES,MACK PUBLISHING CO.,EASTON,PENNSYLVANIA(1975),AND LIBERMAN,H.A.AND LACHMAN,L.,EDS.,Pharmaceutical Dosage Forms,Marcel Decker,NewYork,N.Y.(1980)。
术语“药学可接受盐”是指保持本发明所用化合物生物有效性和性质盐。不是生物学的或不合需要。
此类盐从无机碱制备,包括但不限于钠,钾,锂,铵,钙和镁盐。源自有机碱的盐包括,但不限于伯级,仲,叔胺盐,取代胺盐包括自然生成的取代胺和环胺,包括异丙胺,三甲胺,二乙胺,三乙胺,三丙胺,乙醇胺,2-二甲氨基乙醇,氨基丁三醇,赖氨酸,精氨酸,组氨酸,咖啡因,普鲁卡因,海巴青霉素,胆碱,甜菜碱,乙亚胺,葡萄糖胺,N-烷基葡萄糖胺,可可碱,嘌呤,哌嗪,哌啶和N-乙基六氢吡啶。可以理解的是可以用其它羧酸衍生物,如羧酸胺,包括羧胺,低烷基羧胺,双(低烷基)羧胺。
活性DRI化合物(或其药学可接受载体)本身即可给药或者以药学组分的形式,其中活性组分与一种或多种可接受载体,赋形剂或稀释剂混合。医学组分可以利用一种或多种含有赋形剂或辅料的可接受载体用常规方法配制,赋形剂或辅料可便于将活性物质加工成药学可用的制剂。配制合适依赖于所选择给药途径。
作为药学配制的一部分,这些化合物可能与其它试剂形成复合物。药学组分可以采用以常规方法制备的片剂或胶囊的形式,例如,加有药学可接受赋形剂如结合剂(例如,预胶化玉米淀粉,聚乙烯吡咯烷酮或羟丙基甲基纤维素);填充剂(例如,乳糖,微晶纤维素或磷酸氢钙;或润滑剂。如果任何形成的一种复合物是水溶性的,那它将可能在在适当的缓冲液中形成,例如,磷酸生理食盐水或其它生理协调性溶液。另一种选择是,若生成的复合物在水相溶剂中溶解性很差的话,其可以与表面活性剂如Tween或聚乙二醇一起配制。从而使化合物和其生理可接受溶解物可以配制以用药。
可注射制剂,例如无细菌水相或油性悬浮液可以利用分散或湿润剂和悬浮剂依据已知技术进行配制。无菌注射制剂可是在无毒的肠胃可接受的稀释剂或溶剂无菌注射溶液或悬浮液,例如,溶于丁二醇的溶液。可以利用的可以接受的载体和溶剂是水,林格氏液(Ringer’s solution)和等压生理食盐水注射液,另外,通常利用无菌固定性油作为溶剂或悬浮介质。为实现此目的,可以应用任何一种品牌的固定性油,包括合成甘油单酯或甘油二酯。另外,脂肪酸如油酸在制备注射制剂时很有用。可以利用二甲替乙酰胺,含有离子和非离子表面活性剂和聚乙二醇。如上所讨论过的溶剂和湿润剂的混合物也很有用。
本化合物可以制备进直肠施药组分如栓剂或灌肠剂中,例如,含有常规栓剂基质,如可可黄油或其它甘油酯。此处所讨论的直肠或阴道化合物的给药所用的栓剂可通过将活性制剂与非矿物油赋形剂,如可可黄油,合成甘油一,二,三酯,脂肪酸或聚乙二醇等常温下为固态但在直肠或阴道温度下为固态,其会在直肠或阴道中熔化,释放出药物。口服的固体配药形式包括胶囊,片剂,药丸,粉末和颗粒。在此类固体配药形式中,本发明的化合物通常与对所示用药途径来说恰当的一种或多种辅料结合在一起。合适的赋形剂包括,例如,填充剂如食糖,包括乳糖,蔗糖,甘露醇,山梨醇;纤维素制剂如,玉米淀粉,小麦淀粉,水稻淀粉,土豆淀粉,凝胶,黄蓍胶,甲基纤维素,羟丙基甲基纤维素,羧甲基纤维素钠和/或聚乙烯吡咯啉酮(PVP)。理想的可以添加崩解剂,如交联聚乙烯吡咯啉酮,琼脂,海藻酸或其盐如藻酸钠。
若给药口服,此化合物可以与乳糖,蔗糖,淀粉粉末,烷酸纤维素酯,云母,硬脂酸,硬脂酸镁,氧化镁,磷酸钠盐和钙盐,硫酸,凝胶,阿拉伯胶,藻酸钠,聚乙烯吡咯啉酮和/或聚乙烯醇,之后为方便给药物将其制成片剂或胶囊。这样的胶囊或片剂可以含有控释释放配方,并以活性化合物分散于羟丙基甲基纤维素中供应。与胶囊,药片和药丸一样,配药中可以含有缓冲剂如柠檬酸钠或碳酸镁或碳酸钙或碳酸氢盐。
药片和药丸还可以额外制备上肠衣。
另一选择是口服给药,药物制剂可以是液体形式,例如,溶液,糖浆或悬浮液,成为药物产品,在应用之前补充水分或其它适当载体。此液体制剂可以利用药学常规方法制备,加入药学可接受添加剂如悬浮剂(例如,山梨醇糖浆,纤维素衍生物或氢化食用油;乳化剂(例如,卵磷脂或阿拉伯树胶);非水溶性载体(例如,杏仁油,油酯或氢化植物油);以及防腐剂(例如,甲基或丙基-P-羟基安息香酸或山梨酸)以及甜味剂,风味剂和香味剂。为治疗目的,肠胃给药的配方可以在水溶性或非水溶性等压无菌注射液或悬浮液中。这些溶液和悬浮液可以从用于口服的配方中的提到可用的含有一种或多种载体或稀释剂的无菌粉末或颗粒制备。化合物可以溶解育水中,聚乙二醇,丙乙醇,乙醇,谷物油,花生油,芝麻油,苯甲醇,氯化钠,和/或各种缓冲液。其它辅料和给药物方式在制药技术中为人所熟知。
可以与生产单剂量形式的载体物质结合活性成分用量的依据病人和特别给药方式而不同。
口服给药的制剂可通过活性化合物的控释恰当的制备。
为吸入给药之用,依据本发明的应用的化合物可以方便的通过压力袋或喷雾器呈递的气溶胶供应给药,应用推进剂,例如二氯二氟甲烷,三氯氟甲烷,二氯四氟乙烷,二氧化碳或其它适合气体。在气溶胶情况下,可通过提供一个阀门给出计量,确定用药单位。例如,瓶罐和储药筒,在吸入器或吹药器可以形成凝胶,其中含有化合物的混合物和适当的粉末基质如乳糖或淀粉。
可以为糖果核提供一层合适肠衣。为实现此目的,可以应用浓缩糖溶液,其可选择性的含有阿拉伯树胶,云母,聚乙烯吡咯啉酮,卡波姆(carbopol gel),胶,聚乙二醇,和/或二氧化钛,漆溶液和合适的有机溶剂或溶剂混合物。可以在药片或糖果肠衣上添加染料或色素用于辨认或对不同活性化合物剂量组合进行分类。
可以口服的药学制剂包括由凝胶制成的配合插入胶囊以及由凝胶制备的柔软,密封的胶囊和塑型剂,如甘油和山梨醇。配合插入胶囊可以含有活性成分,其活性成分与填充剂如乳糖,粘合剂,凝结剂如淀粉,和/或润滑剂如云母或硬脂酸镁和选择性稳定剂。在软胶囊中,活性成分可以溶解或悬浮在适当的液体中,例如脂肪酸,液体石蜡,或液体聚乙二醇。另外,可以加入稳定剂。所有口服给药的配方应该对此给药物而言剂量适当。口服给药,组分应该以常规方法配制的片剂或菱形形式。可以配制化合物通过肠胃外给药,例如通过弹丸式注射或持续输液。注射配方应该是单位剂量形式,例如,以一次用量的针剂或多剂量容器形式,并加有防腐剂。组分可以采用在油性或水性载体的悬浮,溶液或乳液的,也可能含有配方成分如悬浮,稳定和/或分散剂。另一种形选择是活性物质应该是粉末状,在应用前与适当的媒介,例如灭菌无热原水组合。
除了以前描述的配方,此化合物也可制备成储存或持久释放的制剂。这样长时间的作用配方应通过灌输,渗透泵或经皮输送(例如,皮下或肌肉间),肌肉间注射,或透皮贴片。例如,这些化合物可以聚合物质或疏水性材料制备(例如,以在可接受油中的乳液形式)或离子交换树脂,或者难溶衍生物,例如,难溶性盐类。
药物组分也含有适当的固体或凝胶相的载体或赋形剂。此类载体或赋形剂包括但不限于碳酸钙,磷酸钙,各种糖,淀粉,纤维素衍生物,凝胶和聚合物,如聚乙二醇。
c.有效剂量
在人身上用的有效的剂量可通过动物模型加以确定。例如,人的剂量可以获取在动物中有效的循环浓度来确定。在技术中公知这些症状的有用动物模型。下类参考特别提供出适当动物疼痛模型。
人所用的有效剂量利用用于治疗抑郁的SNRI化合物的人体数据来确定。给药量可以与治疗抑郁给药量一致。例如,预防抑郁的米那普仑(milnacipran)的给药量的范围是50mg-100mg/天,或者治疗FSD,治疗优选浓度在100mg/天,治疗最优选200mg/day。SNRI化合物的病人口服给药的剂量通常范围为从1μg-1gm/天。例如,为治疗FSD,米那普仑(milnacipran)的剂量范围通常为25mg-400mg/day,更优为100mg-250mg/天。用药可以每天一次或几次或多次。SNRI的量当然与正在治疗接受治疗受测者有关,痛苦严重程度,给药方式和开处方的医师的判断有关。
Claims (26)
1.一种预防或治疗应激相关障碍的方法,包括对有进展为应激相关障碍危险或患有应激相关障碍的病人给药有效剂量的药学化合物,药物化合物选自双重再摄取抑制剂(DRI)药物化合物和三重再摄取抑制剂(TRI)药物化合物用于延迟或预防应激相关障碍发作或缓解应激相关障碍发作症状。
2.根据权利要求1的方法,其特征在于DRI是SNRI化合物。
3.根据权利要求1的方法,其特征在于DRI是NSRI化合物。
4.根据权利要求1的方法,其特征在于DRI化合物有NMDA拮抗活性。
5.根据权利要求3的方法,其特征在于NSRI化合物有NMDA拮抗活性。
6.根据权利要求2的方法,其特征在于SNRI化合物选自度洛西汀(duloxetine)和文拉法新(venlafaxine)。
7.根据权利要求5的方法,其特征在于NSRI化合物是米那普仑。
8.根据权利要求1的方法,其特征在于TRI化合物有NMDA拮抗活性。
9.根据权利要求1的方法,其特征在于TRI是曲美(Sibutramine)。
10.根据权利要求1的方法,其特征在于压力相关性疾病是功能性躯体障碍。
11.根据权利要求1的方法,其特征在于FSD或FSD症状选自MTH,IBS,AFP,PMDD,TMD,NCCP,MCS,LBP,IC和CPP。
12.根据权利要求1的方法,其特征在于药物化合物给药时加有试剂,试剂选自加巴喷丁(neurontin),普加巴林(pregabalin),普拉克索(Pramipexole),左多巴(L-DOPA安非他明(amphetamine),替扎尼定(Tizanidine),可乐亭9clonidine),曲马多(tramadol),吗啡(morphine),三环抗抑郁药(tricyclic antidepressants),可待因(codeine),卡母巴马泽啡(cambamazepine),曲美(Sibutramine),安非他明(amphetamine),安定(valium),查诺顿(Trazodone)。
13.根据权利要求1的方法,其特征在于应激相关障碍选自焦虑,创伤后应激障碍和海湾综合症。
14.根据权利要求7的方法,其特征在于给药量的范围是每天约25mg到约400mg。
15.根据权利要求14的方法,其特征在于给药量的范围是每天约100mg到约250mg。
16.根据权利要求7的方法,其特征在于米那普仑制备成缓释用药配。
17.根据权利要求1的方法,其特征在于药物化合物给药至应激原消除。
18.根据权利要求1的方法,其特征在于药物化合物给药2周。
19.根据权利要求1的方法,其特征在于药物化合物给药6个月。
20.根据权利要求1的方法,其特征在于药物化合物给药一年或多年。
21.根据权利要求1的方法,其特征在于在压力事件发生前化合物给药。
22.根据权利要求1的方法,其特征在于在压力事件发生时化合物给药。
23.根据权利要求1的方法,其特征在于在压力事件发生后不久化合物给药。
24.根据权利要求1的预防或治疗FSD方法,通过一种或多种途径校正障碍,障碍选自神经递质障碍,HPA障碍和神经内分泌障碍。
25.根据权利要求1方法,预防或治疗患有一种或几种FSD症状的人,方法是对个人给药种或多种SNRI药学化合物来治疗一种或多种症状,症状选自慢性疼痛,神经递质变化,神经内分泌变化,睡眠困扰和疲劳。
26.根据权利要求1方法,预防或治疗患有一种或几种FSD症状的人,方法包括同时治疗至少一种FSD的躯体症状和CNS症状。
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