CN1708302A - 睡眠呼吸暂停的药理学疗法 - Google Patents
睡眠呼吸暂停的药理学疗法 Download PDFInfo
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- CN1708302A CN1708302A CNA200380102535XA CN200380102535A CN1708302A CN 1708302 A CN1708302 A CN 1708302A CN A200380102535X A CNA200380102535X A CN A200380102535XA CN 200380102535 A CN200380102535 A CN 200380102535A CN 1708302 A CN1708302 A CN 1708302A
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- serotonin
- sleep
- norcisapride
- cisapride
- serotonin receptor
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Abstract
本发明一般涉及通过给予具有与血清素相关的药理学活性的试剂或这些试剂的组合来预防或改善与睡眠相关的呼吸紊乱的药理学方法。
Description
本申请要求2001年12月14日申请的美国专利号10/016,901的优先权,它要求了2000年8月23日申请的美国专利号09/622,823的优先权,2001年12月18日公开的现在美国专利号6,331,536,它要求了1999年2月26日申请的国际专利申请号PCT/US99/04347的优先权,它要求了美国临时专利申请号60/076,216的优先权,它们的全部内容引入这里作为参考。
发明背景
发明领域
本发明一般涉及呼吸紊乱的药理学疗法,更具体地说,涉及给予具有与血清素相关的受体活性的试剂或组合物来减轻睡眠呼吸暂停(中枢性和阻塞性)及其它与睡眠相关的呼吸紊乱。
相关技术
在过去几年中,已经对主要在睡眠期间发生的呼吸紊乱的离散群体研究作出了许多努力,结果困倦形式持续贯穿清醒时段,因此表明它本身带来了实质的经济损失(如数以千计的人时损失)或职业安全因素(如在重型机器的操作过程中雇员不专心)。与睡眠相关的呼吸紊乱的特征是呼吸反复减少(呼吸浅慢)、周期性呼吸停止(呼吸暂停)或通气连续或持续减少。
通常睡眠呼吸暂停被定义为在睡眠期间鼻和口气流的间歇性停止。按照惯例,认为呼吸暂停持续时间至少10秒就已经很重大了,但是多数个体的呼吸暂停持续时间是20-30秒并可以长达2-3分钟之久。而应该认为在临床上重要的是关于呼吸暂停的最小次数有一些不确定性,到多数个体引起医学团体注意时,他们每小时睡眠具有至少10至15次事件。
睡眠呼吸暂停已被分为三个类型:中枢性、阻塞性和混合性。在中枢性睡眠呼吸暂停中,全部呼吸肌的神经驱动短暂消失。在阻塞性睡眠呼吸暂停中,由于口咽气道阻塞导致,尽管有连续呼吸驱动,然而气流停止。中枢性呼吸暂停继之以阻塞性因素组成的混合性呼吸暂停是阻塞性睡眠呼吸暂停的变型。最常见的呼吸暂停类型是阻塞性睡眠呼吸暂停。
在多至24%的工作成年男性和9%的类似女性中鉴定到阻塞性的睡眠呼吸暂停综合征(OSAS),高峰流行在第六个十年。几乎是OSAS的恒定特征的习惯性重度打鼾已经在达24%的中年男人、14%的类似年龄的女性中述及,甚至在更年长的人中更流行。
阻塞性的睡眠呼吸暂停综合征的决定性事件是上气道阻塞,常常在口咽水平。造成的呼吸暂停通常导致渐进型窒息直到个体暂时从睡眠状态唤醒,因此恢复气道开放并因此恢复气流。
在OSAS中,导致上气道塌陷的一个重要因素是吸气动作期间临界负压的产生超过了气道扩张肌和展肌维持气道稳定性的能力。睡眠通过降低上气道肌肉包括扩张肌和展肌的活动而起着关键作用。
在多数OSAS个体中,在结构上也损害了气道的开放并因此易于阻塞。在少数个体中,结构上的损害通常是由于明显的解剖学异常,即腺扁桃体(adenotonsillar)肥大、下颌退缩症或舌肥大。然而,在易患OSAS的大多数个体中,结构异常只不过是微妙的气道大小减小,即“咽拥堵”。肥胖也常常有助于在上气道中见到的大小减小。打鼾动作实际上是上气道腔大小减小造成的腭和咽软组织的高频振动,软组织水肿的产生通常加剧狭窄。
成为OSAS特征性的夜间窒息和从睡眠中唤醒的循环发作导致一系列继发的生理事件,它依次引起该综合征的临床并发症。最常见的表现形式是神经精神和行为紊乱,认为它们起因于循环唤醒反应诱发的睡眠打破和慢波睡眠损失。夜间脑组织缺氧也可能起重要作用。最普遍的表现形式是白天过度困倦。OSAS现在被公认为白天困倦的主要原因并且已经暗示成为如机动车事故这种问题的重要危险因素。其它相关症状包括智力损害、记忆丧失、人格障碍和阳萎。
另一个主要表现形式本质上是心呼吸性质的并且认为起因于夜间窒息的循环发作。多数个体表现出呼吸暂停期间心率周期性减慢至每分钟搏动30至50次,随后是通气期间每分钟搏动90至120次的心动过速。少数个体发展为持续时间8至12秒心搏停止的严重心动过缓或危险的心律失常,包括非持续性的室性心动过速。OSAS也加剧具有基础心脏病的患者左心室衰竭。这个并发症很可能是由于在每个阻塞事件过程中左心室后负荷增加、继发胸内负压增加、反复的夜间低血氧症和长期性肾上腺交感活动增加的综合效应。
中枢性睡眠呼吸暂停作为综合征不如OSAS那样流行,但是可以在与每日肺泡通气过低或与周期性呼吸相关的医学、神经病学和/或神经性肌肉障碍的广大范围的患者中鉴定到。中枢性睡眠呼吸暂停中的决定性事件是呼吸肌中枢驱动的短暂消失。产生的呼吸暂停引起类似于OSAS的主要顺序事件。几个基础机制可以导致睡眠期间呼吸驱动停止。首先是代谢性呼吸调节系统和呼吸神经肌肉装置的缺陷。其它中枢性睡眠呼吸暂停紊乱起因于另外的完好呼吸调节系统的短暂不稳定。
很多健康的个体表现出睡眠期间少量的中枢性呼吸暂停,特别是在睡眠开始和REM睡眠中。这些呼吸暂停与任何生理或临床紊乱没有联系。在临床上有重大中枢性睡眠呼吸暂停的个体中,赋予紊乱特性的主要顺序事件引起显著的生理和临床结果。在中枢性睡眠呼吸暂停肺泡通气过低综合征的个体中,白天高碳酸血症和低血氧症通常明显,并且这个临床现象受循环呼吸衰竭、红细胞增多症、肺动脉高压和右心衰竭史支配。睡眠差、晨起头痛、白天疲劳和困倦的报怨也突出。相反,在由于呼吸驱动不稳定而造成中枢性睡眠呼吸暂停的个体中,这个临床现象受与睡眠紊乱相关的特征支配,包括反复的夜间唤醒、早晨疲劳和白天困倦。
目前,对于有睡眠呼吸暂停及其它与睡眠相关的呼吸紊乱的成年人,最常见和最有效的疗法是输送气道正压(PAP)的机械形式疗法。在PAP疗法下,个体在睡眠时鼻子上戴着一个紧密装配的塑料面具。这个面具与压缩机连接,压缩机迫使空气进入鼻子,在患者气道内产生正压。这个方法的原理是给气道加压以提供机械“夹板”作用,预防气道塌陷,因此预防阻塞性睡眠呼吸暂停。在经受PAP疗法的多数患者中观察到了有效的治疗反应,但是很多患者不能忍受那个装置或压力并拒绝治疗。此外,最近隐蔽的监视器研究清楚地证明PAP疗法的长期顺从性很差。
已经尝试了将各种上气道和颅面手术方法用于治疗OSAS。腺扁桃体切除术看来是很多儿童OSAS的有效疗法,但是上气道手术对OSAS成人患者很少有治病效力。手术“成功”通常是指呼吸暂停的发生率减少了50%,没有有效的用来鉴定将受益于手术的个体和不能得到益处的个体的筛选法。
在睡眠呼吸暂停患者中,已经尝试了几种类型的药理学疗法,但是迄今无一疗法被证明是通常有效的。Hudgel[J.Lab.Clin.Med.,126:13-18(1995)]提供了这些尝试的新近的系统性综述。由于它们的预期的呼吸兴奋剂性质,已经测试了很多化合物。这些包括(1)乙酰唑胺,一种对原发性中枢性呼吸暂停个体产生可变改善的但是引起阻塞性呼吸暂停增加的碳酸酐酶抑制剂,(2)甲羟基孕酮,一种证明对OSAS无稳固益处的孕酮,和(3)茶碱,一种通常用于治疗哮喘的化合物,它可能有益于中枢性呼吸暂停患者,但是看来对阻塞性呼吸暂停的成人患者无益。
其它尝试的药理学疗法包括给予腺苷、腺苷类似物和腺苷再摄取抑制剂(美国专利号5,075,290)。具体地说,已经表明一种体内普遍存在的化合物并且在OSAS个体中其水平增加的腺苷能刺激呼吸并且在减少睡眠呼吸暂停动物模型的呼吸暂停中有某些效果。
其它可能的OSAS药理学疗法选择包括刺激脑活动的试剂或鸦片样物质拮抗剂。具体地说,已经在OSAS中鉴定到脑脊液鸦片样物质的活性增加,合乎逻辑的结论是中枢性激动剂或鸦片样物质拮抗剂将是对OSAS有益的疗法。事实上,发现刺激中枢神经系统和颈动脉体化学感受器的吗啉吡咯酮可减少患有阻塞性睡眠呼吸暂停个体的呼吸暂停持续的时间,但是不改变平均的动脉血氧饱和度。已知刺激通气的鸦片样物质拮抗剂-纳洛酮在阻塞性睡眠呼吸暂停个体中仅仅稍微有益。
因为OSAS与高血压的发生有密切关系,所以试剂如血管紧张素转换酶(ACE)抑制剂可能在治疗具有高血压的OSAS个体中有益,但是这看来不是OSAS本身的可行疗法。
最后,在OSAS个体中测试了作用于参与呼吸的神经递质和神经递质系统的几种试剂。这些化合物中的大多数已经被开发为通过增加单胺神经递质,包括去甲肾上腺素、多巴胺和血清素活性而工作的激动剂药物。在几个小试验中测试了一种三环激动剂-普罗替林具有可变的以及频繁和显著的副作用。由于血清素可以促进睡眠和刺激呼吸,已经在OSAS个体中测试了色氨酸-一种血清素前体和选择的血清素再摄取的抑制剂。虽然一项专利已经发表了血清素再摄取抑制剂-氟苯氧丙胺的用途(美国专利号5,356,934),但是初步的证据提示这些化合物仅仅在大约50%的OSAS个体中可以产生可测定的益处。因此鉴于事实-罹患与睡眠相关的呼吸紊乱个体的唯一可行的疗法是机械形式的疗法(PAP),其中患者顺从性低,而且希望药理学疗法仍成为现实,所以需要对罹患与睡眠相关的呼吸紊乱的广泛的基础个体提供益处的基于简单药理学的疗法。也需要将高比率的患者顺从性给予它的与睡眠相关的呼吸紊乱的可行疗法。
发明概述
本发明涉及提供预防或改善与睡眠相关的呼吸紊乱的药理学疗法。
本发明涉及预防或改善与睡眠相关的呼吸紊乱的方法,该方法包括给需要这种疗法的患者施用有效量的血清素受体拮抗剂。本发明还涉及包括给予血清素受体拮抗剂的组合来预防或改善与睡眠相关的呼吸紊乱的方法。血清素受体拮抗剂的组合可以指单一的血清素受体亚型或一个以上的血清素受体的亚型。
本发明进一步涉及包括给予血清素受体拮抗剂的组合以及与血清素受体激动剂一起的组合来预防或改善睡眠相关呼吸紊乱的方法。血清素受体拮抗剂的组合以及受体激动剂的组合可以指单一的血清素受体亚型或一个以上的血清素受体亚型。
本发明还涉及包括给予血清素受体拮抗剂的组合以及与α2肾上腺素能受体亚型拮抗剂一起来预防或改善与睡眠相关的呼吸紊乱的方法。血清素受体拮抗剂的组合可以指单一的血清素受体亚型或一个以上的血清素受体亚型。
前述方法的给药途径可以通过任何全身方法,包括口腔、腹腔内、皮下、静脉内、肌内、经皮或通过其它给药途径。也可以使用渗透小泵和定时释放小丸或其它给药储库形式。唯一的限制是给药途径导致药理学试剂最终递送至适当的受体。
与睡眠相关的呼吸紊乱包括但不限于阻塞性睡眠呼吸暂停综合征、早熟性呼吸暂停、先天性中枢性通气不足综合征、肥胖性通气不足综合征、中枢性睡眠呼吸暂停综合征、Cheyne-Strokes呼吸和机鼾。
血清素受体拮抗剂可以使用其游离碱形式或季铵盐形式。通过叔氮原子转变为与反应性卤代烃类,例如甲基碘、乙基碘或各种苄基卤化物的季铵盐,这些血清素受体拮抗剂发生季铵化反应。已经表明有些血清素拮抗剂的季铵化形式,具体地说,甲基化的zatosetron缺乏通过血脑屏障的能力(Gidda et al.,J.Pharmacol.Exp.Ther.273:695-701(1995)),并且因此仅仅在周围神经系统起作用。血清素受体拮抗剂局限于化合物本身及其药学上可接受的盐之一。
示例性的血清素受体拮抗剂包括但不限于游离碱形式或季铵化形式的zatosetron、曲匹西隆、多拉司琼、氢化多拉司琼、仙人球毒碱、苯呋噁庚胺、高氯环、哌拉平、奥丹西隆(GR38032F)、酮色林、克塞平、奥氮平、氯丙嗪、氟哌啶醇、r(+)奥丹西隆、西沙比得、norcisapride、(+)西沙比得、(-)西沙比得、(+)norcisapride、(-)norcisapride、去甲奥氮平、2-羟甲基奥氮平、1-(2-氟苯)-3-(4-羟氨乙基)-丙-2-烯-1-酮-O-(2-二甲基氨基乙基)-肟、利司哌酮、塞庚啶、氯氮平、甲基麦角新酯、格雷西龙、米塞林、利坦色林、肉桂硫胺、LY-53,857、麦角苄酯、LY-278,584、美赛西平、p-NPPL、NAN-190,哌嗪、SB-206553、SDZ-205,557、3-托烷基-吲哚-3-羧化物、3-托烷基-吲哚-3-羧化甲碘化物和其它血清素受体拮抗剂及其四元形式或其药学可接受盐之一。
示例性的血清素受体激动剂包括但不限于8-OH-DPAT、舒马曲坦、L694247(2-[5-[3-(4-甲基硫酸氨基)苄基-1,2,4-噁二唑-5-yl]-1H-吲哚-3yl]乙醯胺)、丁螺环酮、alnitidan、zalospirone、伊沙匹降、吉吡隆、佐米曲坦、risatriptan、311C90、α-Me-5-羟色胺、BW723C86(1-[5(2-噻吩基甲氧基)-1H-3-吲哚基[丙烷-2-胺盐酸盐)、和MCPP(间-氯苯基哌啶)。血清素受体激动剂局限于化合物本身及其药学可接受盐之一。
示例性的α2肾上腺素能受体拮抗剂包括但不限于tophenoxybenzamine、酚妥拉明、妥拉苏林、特拉唑嗪、多沙唑嗪、三甲氧唑啉、育亨宾、吲哚拉明、ARC239和哌唑嗪或其药学可接受盐之一。
示例性的选择性血清素再摄取抑制剂包括但不限于氟苯氧丙胺、帕罗西汀、三氟戊肟胺、舍曲林、西酞普兰、去甲氟西汀、r(-)氟苯氧丙胺、s(+)氟苯氧丙胺、脱甲基舍曲林、脱甲基西酞普兰、文拉法新、milnacipran、西布曲明、奈法唑酮、R-羟基奈法唑酮、(-)文拉法新和(+)文拉法新。选择性血清素再摄取抑制剂定义是化合物本身及其药学可接受盐之一。
附图简述
图1阐明了与对照相比,血清素拮抗剂GR38032F(奥丹西隆)对非快速眼动(NREM)睡眠的每小时呼吸暂停比率的影响。图上每个数据点表示9只大鼠的平均数±标准误(p=0.007对对照)。
图2显示了与对照相比,血清素拮抗剂GR38032F(奥丹西隆)对NREM睡眠占总记录时间百分比的影响。每个数据点表示9只大鼠的平均数±标准误差(p=0.0001对对照)。
图3显示了与对照相比,血清素拮抗剂GR38032F(奥丹西隆)对快速眼动(REM)睡眠的每小时呼吸暂停比率的影响。每个数据点表示9只大鼠的平均数±标准误差(p=0.01对对照)。
图4阐明了与对照相比,血清素拮抗剂GR38032F(奥丹西隆)对REM睡眠占总记录时间百分比的影响。每个数据点表示9只大鼠的平均数±标准误差。
图5显示了与对照相比,血清素拮抗剂GR38032F(奥丹西隆)对清醒、NREM和REM睡眠期间标准化的每分通气量的比率的影响。每个数据条表示混合的所有动物(n=9)在6个记录时间的平均数±标准误差(给予GR38032F后,在所有行为状态下,每分通气量明显变大;p<0.03对对照)。
图6显示了血清素(0.79mg/kg)、GR38032F(0.1mg/kg)+血清素(0.79mg/kg),和GR38032F(0.1mg/kg)对NREM睡眠时自发呼吸暂停的影响。每个数据条表示对于所有动物(n=10;p=0.97)在6个记录时间的平均数±标准误差。
图7阐明了血清素(0.79mg/kg)、GR38032F(0.1mg/kg)+血清素(0.79mg/kg),和GR38032F(0.1mg/kg)对REM睡眠期间自发呼吸暂停的影响。每个数据条表示对于所有动物(对于给予血清素对对照,n=10;p=0.01;对于给予GR38032F+血清素对单独的血清素,p=0.05;对于给予GR38032F+血清素对对照,p=0.99;和对于单独给予GR38032F,p=0.51)在6个记录时间的平均数±标准误差。
发明详述
以前的针对在几种麻醉(见下文)的动物种类中,对于血清素或血清素类似物对呼吸的影响的研究证明了可变的反应。例如,已经表明给予血清素可引起兔的呼吸速率增加,潮气量减少,但是引起狗的潮气量增加[Matsumoto,Arch.Int Pharmacodyn.Ther.,254:282-292(1981);Armstrong et al.,J.Physiol.(lord.),365:104P(1985);Bisgard et al.,Resp.Physio.37:61-80(1979);Zucker et al.Circ.Res.47:509-515(1980)。在猫的研究中,给予血清素产生的通气过度偶尔先于呼吸暂停[Black et al.,Am.J.Physiol.,223:1097-1102(1972);Jacobs et al.,Circ.Res.,29:145-155(1971)],或直接的呼吸暂停之后是快速的浮浅呼吸[Szereda-Przestaszewskaet al.,Respir.Physio.,101:231-237(1995)]。
给予2-甲基-5-羟色胺,一种选择性5-羟色胺3受体激动剂,在猫研究中引起呼吸暂停[Butler et al.Br.J.Pharmacol.,94:397-412(1988)]。静脉内给予血清素、2-甲基-5-羟色胺或高剂量的a-甲基-5-羟色胺、5-羟色胺2受体激动剂产生了短暂呼吸暂停,其持续时间以剂量依赖性方式增加。GR38032F(1,2,3,9-四氢-9-甲基-3-[(2-甲基咪唑-1-基)甲基]咔唑-4-酮、盐酸盐、二水合物)-一种选择性5-羟色胺3受体拮抗剂显著地对抗这个反应[Butler et al.Br.J.Pharmacol.,94:397-412(1988);Hagan et aL,Eur.J.Pharmacol.,138:303-305(1987)]以及烷丝氨酸和甲基麦角新酯、5-羟色胺2受体拮抗剂[Yoshioka et al.,J.Pharmacol.Exp.Tirer.,260:917-924(1992)]。在新生大鼠中,给予活化中枢性血清素生物合成的血清素前体-L-色氨酸产生了阻塞性呼吸暂停的反复发作,经常后面跟随中枢性呼吸暂停[Hilaire et al.,J.Physio.,466:367-382(1993);Morin,Neurosci.Lett.,160:61-64(1993)]。
尽管前述研究揭露了关于在呼吸暂停的开发中包含血清素的重要信息,如上所述所有这些研究的一个显著的问题是动物被麻醉,和因此获得的任何结果不能归因于具体的血清素激动剂或拮抗剂,即麻醉或与麻醉相关的异常生理条件之间的相互作用不能被排除。
血清素受体的活性也可能促进与自发睡眠相关的中枢性呼吸暂停,它已经在大鼠中报道,[Mendelson et al.,Physio.Behav.,43:229-234(1988);Sato et al.Am.J.Physio.,259:R282-R287(1990);Monti et al.,Pharmacol.Biochem.Behav.,125-131(1995);Montiet al.,Pharmacol.Biochem.Behav.,53:341-345(1996);Thomaset al.,.J.Appl.Physio.,78:215-218(1992);Thomas et al.,J.Appl.Physio.,73:1530-1536(1995);Carley et al.Sleep,19:363-366(1996);Carley et al.,Physiol.Behav.,59:827-831(1996);Radulovacki et al.,Sleep,19:767-773(1996);Christonet al.,J.Appl.Physiol.,80:2102-2107(1996)]。为了检验这个假说,为了估计血清素受体的阻断是否将抑制NREM睡眠和REM睡眠期间的自发性呼吸暂停表现,进行实验以测试自由活动动物中血清素拮抗剂的作用。为了估计外周血清素受体的血清素激活活性增加是否可以促进睡眠呼吸暂停,也进行实验以测试自由活动动物中血清素和血清素拮抗剂的单独和联合的作用。
下列实施例阐明了给予血清素受体拮抗剂,尤其是GR38032F引起非快速眼动(NREM),尤其是快速眼动(REM)睡眠期间的中枢性呼吸暂停的抑制作用。这个作用与呼吸驱动的增加相关,但是在测试的剂量下没有引起心血管的变化。
下列实施例也阐明了给予血清素诱发自发呼吸暂停表现的作用,通过给予血清素受体拮抗剂,尤其是GR38032F可完全拮抗这个作用。
下列实施例进一步描述了最适合单一的试剂或试剂的组合以成功地预防或改善与睡眠相关的呼吸紊乱的药理学概况,即
(a)具有5-羟色胺2或5-羟色胺3受体亚型拮抗活性或两种活性都有的单一试剂或试剂组合;
(b)具有5-羟色胺2或5-羟色胺3受体亚型拮抗活性或两种活性都有,以及与5-羟色胺或5-羟色胺2受体亚型激动活性或两种活性都有的单一试剂或试剂一起的组合;或
(c)具有5-羟色胺2或5-羟色胺3受体亚型拮抗活性或两种活性都有,连同α2肾上腺素能受体亚型拮抗活性的单一试剂或试剂一起的组合;
本发明和实施方案的更多方面对本领域技术人员来说将是显而易见的。为了充分理解本发明,提供下列实施例仅作为例证而不作为限制。
实施例1描述了用于用血清素拮抗剂或激动剂或二者同时治疗动物的准备和随后的生理记录和测试。
实施例2描述了治疗动物和对照动物的生理记录方法,和给予血清素拮抗剂获得的结果。
实施例3描述了给予血清素,随后给予血清素受体拮抗剂而获得的结果。
实施例4描述了具有特殊的与血清素相关的药理活性的用于有效地抑制或预防与睡眠相关的呼吸紊乱的试剂或组合物。
下列实施例阐明了本发明的方面,但是不能被解释成限制本发明。
实施例1
用于生理试验和记录的动物的准备
将成年雄性Sprague-Dawley大鼠(Sasco-King,Wilmington,MA;通常每个试验组8只;300g)维持在一周12小时光明(08:00-20:00小时)/12小时黑暗(20:00-08:00小时)的循环中,圈养在单独的笼中并随意获得食物和水。驯化一周后,让动物接受下列手术程序。
使用氯胺酮(Vedco,Inc.,St.Joseph,MO;100mg/ml)和乙酰丙嗪(Vedco,Inc.,St.Joseph,MO;10mg/ml;4∶1,体积/体积)以1ml/kg体重的体积麻醉驯化的动物,植入皮层电极进行脑电图(EEG)记录,植入颈部肌肉电极进行肌电流图(EMG)记录。通过手术暴露头颅表面并用20%过氧化氢溶液清洁,随后用95%异丙醇溶液清洁。接下来,应用氟化钠牙制剂(Flura-GELO,Saslow Dental,Mt.Prospect,IL)硬化顶骨皮层上面的颅骨并允许留在那个位置达5分钟。然后从顶骨皮层上面的颅骨上除去氟化混合物。由四个不锈钢机器螺钉组成,有导线与之连接的EEG电极穿过颅骨停留在顶骨皮层的硬膜上。应用薄层Justi树脂胶合剂(Saslow Dental,Mt.Prospect,IL)涂抹螺钉头(埋入颅骨的螺钉)并包裹颅骨以进一步促进植入物的粘附。由两个球形钢丝组成的EMG电极被插入两侧的颈部肌肉系统。所有导线(即EEG和EMG导线)被焊接到小型连接器(39F1401,Newark Electronics,Schaumburg,IL)。最后,用牙粘合剂将全部部件固定到颅骨上。
手术后,允许所有动物恢复一周后,接受包括植入无线电遥测发送器的另一个手术(TAl1-PXT,Data Sciences International,St.Paul,MN)以监测血压(BP)和心动周期(HP),估计如同搏动周期。麻醉动物(如上所述)后,除去剑突下间隙至骨盆的毛发。用碘酒擦洗全部区域并用酒精和盐冲洗。实施4-6cm中线剖腹术以允许从主动脉至肾动脉分叉区域有好的可视区。牵引器用来暴露腹部内容并用盐水湿润的纱布棉拭拦阻肠管。用无菌卷棉子将主动脉与包裹的脂肪和结缔组织剖开。3-0丝缝线置于主动脉之下,给缝线施加牵引力以限制血流。然后用钳子握住植入物(TAl1-PXT),同时用21-规格针在坡口端刺穿主动脉,仅从头颅至分叉处。导管尖端插入针下,用针作为引导直到薄壁BP传感器部分处于容器的内部。最后,将一滴组织粘合剂(Vetbondg,3M,Minneapolis,MN)应用于穿刺部位并用一小方块纤维素纤维(大约5mm2)覆盖以便封闭导管插入后的穿刺口。用3-0丝缝线将放射性植入物粘附于腹壁,逐层封闭切口。在第二次手术后,再次允许动物恢复一周时间,之后给予血清素受体拮抗剂和随后的生理记录。
实施例2
呼吸暂停的生理记录和抑制
以随机顺序在2个时机记录每只动物的生理参数(见下文),各个动物的记录分开至少3天。在每一记录前十五分钟,让每只动物接受盐水(对照)或1mg/kg奥丹西隆(GR38032F;1,2,3,9-四氢-9-甲基-3-[(2-甲基咪唑-1-基)甲基]咔唑-4-酮,氢氯化物,二水合物;Glaxo Wellcome,Inc.Research Triangle Park,NC)全身注射(1ml/kg腹膜内快速浓注)。从10:00-16:00进行多波动记录。
将每只动物自由放置在新鲜房间空气以2L/分钟的速度偏流通风的单一室体积描记器内部(PLYUNlR/U;Buxco Electronics,Sharon,CT;dimension 6 in.x 10 in.x 6 in.)。塞在动物连接器上并通过封闭端口的电缆用于携带来自头部植入物的生物电活动。呼吸、血压、EEG活动和EMG活动显示在视频监视器上,同时以每秒100次数字化并存储在计算机磁盘上(Experimenter′s Workbench;DatawaveTechnologies,Longmont,CO)。
用双顶骨EEG和颈EMG信号以10秒出现时间估计睡眠和清醒状态,如Bennington et al.[Sleep,17:28-36(1994)]所述。这个软件以高频低振幅EEG和伴随的高EMG基调来鉴别清醒(W),以主轴和θ活动增加连同EMG基调降低来鉴别NREM睡眠,和以δ与θ活动的低比率和缺乏EMG基调来鉴别REM睡眠。将睡眠效率测量为NREM或REM睡眠占总的记录出现时间的百分比。
被认可的自发睡眠呼吸暂停的生理学动物模型[大鼠;Monti,etal.,Pharamcol.Biochem.Behav.,51:125-131(1995)]用于估计GR38032F的作用。更具体地说,对每个记录期间定义为呼吸工作停止至少2.5秒的睡眠呼吸暂停进行打分,并与它们所发生的睡眠阶段联系起来:NREM或REM睡眠。
2.5秒的持续时间要求表示至少2次“错过”的呼吸,因此它类似于在人类中的10秒呼吸暂停持续时间要求,它还反映2-3次错过的呼吸。检测到的事件代表中枢性呼吸暂停,因为与阻塞或闭合气道相关的通气降低将使体积描记信号而不是暂停增加。呼吸暂停指数(AI),被定义为在一个阶段中每小时的呼吸暂停,分别确定NREM和REM睡眠的呼吸暂停指数。使用ANOVA利用重复测量来检测睡眠阶段(NREM对REM)的作用和注射(对照对GR30832F)的作用。使用Fisher′s的受保护的最小显著性差异(PLSD)来控制多重比较。此外,通过自动分析(Experimenter s′Workbench;Datawave Technologies,Longmont,CO)对每次呼吸的时间和体积进行打分。对于每只动物,计算W的平均呼吸速率(RR)和每分钟通气量(MV),贯穿6个小时对照记录,并用作将在那只动物中在睡眠和给予GR38032F期间的呼吸标准化的基线。也通过非参数(Kruskal-Wallis)分析来实施单因素ANOVA。在所有情况下,使用参数和非参数ANOVA的结论相同。
采用类似软件(Experimenters′ Workbench;DatawaveTechnologies,Longmont,CO)分析血压波形;对于每个记录的每次搏动,测定心脏收缩(SBP)和心脏舒张(DBP)的血压和脉冲间隔。脉冲间隔提供搏动之间HP的估计值。根据每次搏动的SBP和DBP的加权平均值估计平均BP(MBP):MBP=DBP+(SBP-DBP)/3。根据睡眠/清醒状态和它们发生期间的记录时间,也对每次搏动的参数进行分类。
有关给予血清素拮抗剂GR38032F对6小时的多波动记录期间NREM睡眠每小时呼吸暂停的比率的结果(见图1)证明治疗或6小时的时间没有显著的作用(双因素ANOVA)。然而,通过配对的t检验测得在记录的前2个小时期间有显著的呼吸暂停抑制(每组p<0.01)。这个呼吸作用与前2个小时期间GR38032F引起的NREM睡眠显著抑制有关,如图2所证明的。给予GR38032F的大鼠在6个小时记录中NREM睡眠的百分比比对照的低,但是这种降低仅在记录的前2个小时达到统计学上的显著性(p<0.001)。
结果进一步表明在贯穿6个小时记录期间,GR38032F对REM睡眠呼吸暂停具有显著的抑制作用(对于药物作用的双因素ANOVA,p=0.01;见图3)。这个作用在前4个小时的记录期间特别明显,在此期间没有动物显示出在REM睡眠中有单一的自发呼吸暂停。这个作用不是前4个小时期间REM抑制的简单反映。
图4列出的结果表明GR38032F不能显著地影响REM睡眠。尽管药物治疗的动物的REM睡眠低于相应的对照动物,但是在全部或任何单一记录时间内,它都达不到统计学上的显著性。
关于给予GR38 032F对标准化的W(清醒)、NREM(非快速眼动)睡眠、和REM(快速眼动)睡眠期间的每分钟通气量的结果(见图5)表明显著地刺激了所有行为状态期间的通气(每组p=0.03)。最后,结果表明GR38032F对测定的任何心血管变量(W、NREM和REM睡眠期间的MBP和HP)没有影响(每个变量p>0.1,见表1)。
表1
GR38032F对心血管变量的影响
平均BP(mm Hg) | HP(毫秒) | |||||
W | NREM | REM | W | NREM | REM | |
对照GR38032F | 111±18113±18 | 110±18112±17 | 10g±18110±17 | 174±5183±3 | 181±5189±3 | 185±6190±3 |
所有值都是平均值±SE。
总的来说,这些结果表明血清素激活系统的操作可以对REM和NREM睡眠中的中枢性呼吸暂停的产生发挥有效的影响。具体地说本发现表明全身给予5-羟色胺3受体拮抗剂抑制自发呼吸暂停表现;腹膜内注射后完全消除了与REM相关的呼吸暂停至少达4个小时。这种呼吸暂停抑制与清醒和睡眠期间观察到的每分钟通气量增加的普通呼吸刺激有关。在不引起心率或血压改变的剂量下观察到这些显著的呼吸影响,甚至在前2个小时期间,当呼吸最大时。
本领域技术人员将认识到游离碱形式或季铵盐形式的示例性的血清素受体拮抗剂包括但不限于(a)酮烷丝氨酸、肉桂硫胺、LY-53,857、麦角苄酯、LY-278,584、美赛西平、p-NPPL、NAN-190、哌嗪、SB-206553、SDZ-205,557、3-托烷基-吲哚-3-羧酸酯、3-托烷基-吲哚-3-羧酸酯甲碘化物、甲基麦角新酯(Research Biochemicals,Inc.,Natick,MA);(b)利司哌酮(Janssen Pharmaceutica,Titusville,NJ);(c)塞庚啶、氯氮平、米塞林、利坦色林(Sigma Chemical Co.,St.Louis,MO);(d)奥丹西隆、格雷西龙(SmithKline Beecham,King of Prussia,PA)、zatosetron、曲匹西隆、多拉司琼和氢化多拉司琼;(e)克塞平、奥氮平、氯丙嗪、氟哌啶醇、r(+)奥丹西隆、西沙比得、norcisapride、(+)西沙比得、(-)西沙比得、(+)norcisapride、(-)norcisapride、去甲奥氮平、2-羟甲基奥氮平、1-(2-氟苯)-3-(4-羟氨基乙基)-丙-2-烯-1-酮-O-(2-二甲基氨基乙基)-肟;(f)仙人球毒碱、苯呋噁庚胺、高氯环和哌拉平及其它血清素受体拮抗剂,它们的任何四元形式或药学可接受盐可以用于预防或改善睡眠相关呼吸紊乱。此外,本领域技术人员也将认识到上述讨论的结果可以容易地与其它哺乳动物联系起来,特别是灵长目(如人)。
实施例3
睡眠呼吸暂停的诱发和抑制
给予血清素或血清素类似物在几个种类麻醉动物中产生了可变的呼吸反应(参见上面,发明详述)。如上实施例2所述,腹腔内给予1mg/kg GR38032F-一种选择性的5-羟色胺3受体拮抗剂抑制了自发的中枢性呼吸暂停。这些作用在REM睡眠中特别显著,在注射后,在REM睡眠期间呼吸暂停完全消失至少4小时。GR38032F的呼吸暂停抑制作用与呼吸驱动增加相平行,但是在测试的剂量下没有BP和心率改变。
在自然睡眠期间GR38032F对自发性呼吸暂停的抑制(见实施例2)与对麻醉大鼠的在先研究一致,其中5-羟色胺和2-甲基-5-羟色胺-选择性的5-HT3受体激动剂驱动了被GR38032F拮抗的中枢性呼吸暂停。由于5-羟色胺不能穿透血脑屏障(BBB),因此这些结果(来自在先研究)表明外周5-羟色胺受体,尤其是5-羟色胺3受体的刺激看来已经驱使了中枢性呼吸暂停的发生。鉴于对麻醉动物实施的那些研究,以及我们对自由活动大鼠的关于给予GR38032F的研究(上面实施例2描述),我们研究了外周5-羟色胺受体,更具体地说5-羟色胺3受体的增加的血清素激活活性促进自发睡眠相关中枢性呼吸暂停的能力,和任何呼吸暂停的诱发是否将对给予5-羟色胺受体拮抗剂引起的拮抗作用敏感。
将成年雄性Sprague-Dawley大鼠(Sasco-King,Wilmington,MA;300g)维持在一周12小时光明(08:00-20:00小时)/12小时黑暗(20:00-08:00小时)的循环中,圈卷在单独的笼中并随意获得食物和水。经过一周驯化后,通过手术程序准备动物以用于生理学测试(即植入皮层电极进行EEG记录和植入颈部肌肉电极进行EMG记录,植入无线电遥测发送器进行BP和HP监测),如上实施例1列出。在手术程序完成后,在允许动物恢复一周时间之后用于本研究。
在四个时机下记录每只动物,各个动物的记录分开至少三天。在每一记录前十五分钟,让每只动物接受(通过腹膜内注射)随机顺序的下列之一:(a)盐水溶液(对照);(b)0.79mg/kg血清素;(c)0.1mg/kg GR38032F加0.79mg/kg血清素;或(d)0.1mg/kg GR38032F。对于GR38032F+血清素测试组,在09:30给予0.1mg/kg GR38032F,随后是09:45给予0.79mg/kg血清素。10:00-16:00进行多波动记录。
通过特别如上面实施例2列出的实验步骤确定和记录呼吸BP、EEG和EMG数据。如实施例2所述,对每个记录期间定义为呼吸工作停止至少2.5秒的睡眠呼吸暂停进行打分,并与它们所发生的睡眠阶段联系起来:NREM或REM睡眠。2.5秒的持续时间要求表示至少两次“错过”的呼吸,它类似于在人中的10秒的呼吸暂停持续时间要求。
使用方差分析(ANOVA)重复测试睡眠阶段(NREM对REM)和注射(对照对给予单独血清素、GR38032F+血清素或单独GR38032F)对呼吸暂停指数、呼吸模式、BP和HP的影响。使用Fisher′s保护的最小显著性差异(PLSD)来控制多重比较。也用非参数(Kruskal-Wallis)分析来实施单因素ANOVA。在所有情况下,使用参数和非参数ANOVA的结论相同。
给予单独血清素(0.79mg/kg)、GR38032F(0.1mg/kg)+血清素(0.79mg/kg)或单独GR38032F(0.1mg/kg)在6小时多波动记录期间促进NREM睡眠中自发呼吸暂停的能力的结果在图6中列出。具体地说,在NREM睡眠期间,自发呼吸暂停指数不受任何药物治疗的影响。
如图7阐明,与对照的记录相比,给予血清素后,在REM睡眠期间自发呼吸暂停表现出显著性增加(增加>250%)。结果也表明通过在先给予GR38032F消除了这种增加。单独给予低剂量测试的(0.1mg/kg)GR38032F对REM睡眠自发呼吸暂停没有影响。
如表2所示(给予药物后,在6小时多波动记录期间清醒、NREM和REM睡眠的百分比),在腹腔内单独给予血清素、GR38032F+血清素或单独GR38032F对睡眠结构没有影响。最后,所测试的治疗组中没有一组对RR、VE、平均BP、HP或PS呼吸暂停指数有显著的影响(数据未显示)。
表2
5-HT和GR38032F对睡眠/清醒结构的影响
%清醒 | %NREM | %REM | |
对照(盐水溶液)5-HT(0.79mg/kg)5-HT+GR38032FGR38032F(0.1mg/kg)p(单因素ANOVA) | 33.7±2.5*30.2±3.236.7±8.728.8±6.40.43 | 58.0±1.959.9±3.356.0+7.663.4±5.70.71 | 6.9±1.16.5±1.15.3±1.47.3±2.30.60 |
*对于每个百分比记录时间,所有的值反映了平均值±SE。
总的来说这些结果表明外周血清素受体的操作对REM睡眠期间的中枢性呼吸暂停的产生发挥有效的影响。具体地说,本结果表明全身给予血清素增加睡眠中自发的呼吸暂停表现。尽管采用的血清素剂量对睡眠、心血管参量、RR或VE没有影响,但是与REM相关的自发呼吸暂停指数的增加>250%。此外,重要的是注意到呼吸暂停发生的机制至少部分是睡眠状态特异性的,因为NREM呼吸暂停不受影响。
这些发现证明,外源给予各种剂量的5-羟色胺3激动剂和拮抗剂产生REM睡眠特异性的呼吸暂停表现的改变。这种发现表明内源血清素激活活性有调节呼吸暂停表现的生理作用,特别是调节REM睡眠期间的呼吸暂停表现。此外,因为血清素不能通过血脑屏障,所以血清素发挥着对GR38032F的逆效应的发现表明相关受体位于外周神经系统。
此外,本数据提示,超过生理水平的血清素对呼吸暂停的活性是受体介导的,因为低剂量(0.1mg/kg)GR38032F预处理不独立地影响任何测定的参数包括呼吸暂停,能完全阻滞外源血清素对呼吸暂停表现的作用。
鉴于前述数据,认为观察到的给予血清素引起呼吸暂停促进作用的外周活性部位可能是迷走神经的结状神经节。更具体地说,几个研究得出结论:Bezold-Jarisch反射的呼吸暂停成分是由在猫结状神经节处血清素的活性引起的(Jacobs et al.,Circ.Res.,29:145-155(1971),Sampson et al.,LifeSci.,15:2157-2165(1975),Sutton,PfllugersArch.,389:181-187(1981)]and rats[Yoshioka et al.,J.Pharmacol.Exp.Ther.,260:917-924(1992)and McQueen et al.,J.Physiol,5073:843-855(1998)]。静脉内给予血清素或5-羟色胺3受体激动剂也刺激肺迷走神经受体[McQueen et al.,J.Physio.,5073:843-855(1998)],它可能显著地有助于外伤性窒息反应。
尽管可能存在种属差异[Black et al.,Am.J.Physio.,223:1097-1102(1972)],但是对大鼠的几个研究证明除了其对迷走神经信号的影响外,血清素也引起颈动脉体化学感受器激动的增加[McQueen et al.,J.Physio,5073:843-855(1998);Sapru et al.,Res.Comm.Chem.Pathol.Pharmacol.,16:245-250(1977);Yoshioka,J.Pharmacol.Exp.Ther.,250:637-641(1989)andYoshioka et al.,Res.Comm.Chem.Pathol.Pharmacol.;---74:39-45(199′1)]和VE增加[McQueen et al.,J.Physio.,5073:843-855(1998);Sapru et al.,Res.Comm.Chem.Pathol.Pharmacol.,16:245-250(1977)]。尽管不能排除化学感受器介导的对呼吸暂停的影响,但是McQueen et al.,J.Physiol.,5073:843-855(1998)的资料强烈地表明在麻醉的大鼠中,静脉内血清素通过迷走神经途径引起呼吸暂停,而化学感受器活化对抗呼吸暂停的发生。
在麻醉动物中血清素诱发的Bezold-Jarisch反射包括呼吸暂停和心动过缓。在采用的剂量下,在6个小时的记录期间,血清素不引起心率或平均BP的改变。在测试的剂量下,被评估为变异系数的搏动至搏动心率和BP易变性也不受血清素的影响。观察到的心血管和呼吸对血清素的反应脱节表明呼吸暂停表现的改变不是压力感受器介导的。
尽管麻醉动物中的Bezold-Jarisch反射和REM睡眠中血清素诱发的呼吸暂停不是相同的现象,但是它们可能通过类似的机制相关联。当用外来手段强烈操作血清素受体时,即用血清素激活激动剂或拮抗剂时,REM睡眠中的自发呼吸暂停表现可以得到增强或抑制。然而,我们观察的1mg/kg GR38032F显著地抑制REM呼吸暂停,不排除5-羟色胺2或其它5-羟色胺受体亚型在外周调节呼吸暂停表现中的作用,以及事实上本发明也设想了使用单独的5-羟色胺2和5-羟色胺3或其组合以及具有2型和3型受体拮抗作用的血清素拮抗剂(见实施例4)。
已经非常确定[Mendelson et al.,Physiol.Behav.,43:229-234(1988);Sato et al.,Am.J.Physio.,259:R282-287(1990);Monti et al.,Pharmacol.Biochem.Behav.,51:125-131(1995);Monti et al.,Pharmacol.Biochem.Behav.,53:341-345(1996);Thomas et al.,J.Appl.Physio.,73:1530-1536(1992)and Thomaset al.,J.Appl.P/lysiol.,78:215-218(1995)]在大鼠中,呼吸暂停频率从深慢波睡眠至浅NREM睡眠至REM睡眠而增加,如同人类的情形。REM睡眠期间呼吸暂停表现的高发生率可能与这种睡眠状态期间发生的呼吸改变有关。典型地,在REM睡眠期间,呼吸变得表浅和不规则[Orem et al.,Respir.Physio.,30:265-289(1977);Phillipson,Annu.Rev.Physio.,40:133-156(1978);Sieck et al.,Exp.Neurol.,67:79-102(1980)and Sullivan,In:Orems et al.,eds.,″Physiology in sleep,″Academic Press,New York,NY,pp.213-272(1980)]和VE处于其最低点[Hudgel et al.,J.Appl.Physiol.,56:133-137(1984)]。与自主活动中强烈的阶段变化联合的这个低呼吸排出量背景[Mancia et al.,In;Orem et al.,eds.,″Physiology in sleep,″Academic Press,New York,NY,pp.1-55(1980)]将致使REM睡眠期间呼吸的体内平衡更易弱化至被呼吸暂停所中断。因此有可能血清素在外周神经系统的活性在REM呼吸暂停发生中的作用可能起因于呼吸传入活动的基调或相位活动受血清素激活的调节,特别是在迷走神经中。因此,REM睡眠期间脑干呼吸的整合区域可能更弱化至受波动的传入输入的影响。
总的来说,这里提供的结果表明,在外周给予血清素产生的REM睡眠期间自发呼吸暂停的恶化是受体介导的。这种发现也表明在基线条件下,外周神经系统的内源血清素在调节睡眠呼吸暂停表现中的生理作用。
实施例4
睡眠呼吸暂停的抑制或预防
如这里提供的数据(见实施例2和3)表明血清素在呼吸暂停的发生中起着重要和整合的作用,是高度部位和受体亚型特异性的。更具体地说,血清素受体拮抗剂抑制呼吸暂停的功效基于其在外周神经系统的活性,迷走神经的结状神经节好象是关键的靶部位。在这个部位的5-羟色胺2和5-羟色胺3受体清楚地与麻醉动物中血清素诱发的呼吸暂停有关[Yoshioka et al,J.Pharmacol.Exp.Therp.,260:917-924(1992)]。连同这些以前的发现,这里提供的数据(将血清素严格地给予外周神经系统加剧了与睡眠相关的呼吸暂停)表明结状神经节的两个类型的血清素受体在睡眠呼吸暂停发病机理中的重要性。
此外,血清素诱发的呼吸暂停表现的增加完全被低剂量GR38032F-5-羟色胺拮抗剂所阻断。这种结果表明前面证明的GR38032F造成的呼吸暂停的抑制(见实施例2)最可能是由于在外周神经系统的活性。
因此,鉴于前述内容,通过全身单独或组合给予具有血清素2型或3型受体拮抗作用的药理学试剂,以及具有血清素2型和3型两型受体拮抗作用的试剂,可以有效地预防或抑制与睡眠相关的呼吸紊乱(睡眠呼吸暂停综合征、婴儿呼吸暂停、Cheyne-Strokes呼吸、与睡眠相关的通气不足综合征)。
预防或抑制与睡眠相关的呼吸紊乱的有效疗法包括全身单独或联合给予5-羟色胺2或5-羟色胺3受体拮抗剂。在优选的实施方案中,血清素受体拮抗剂仅仅在外周神经系统中具有活性和/或不能通过血脑屏障。在更优选的实施方案中,血清素受体拮抗剂显示出5-羟色胺2和5-羟色胺3受体亚型的拮抗作用。
与睡眠相关的呼吸紊乱的当前药理学疗法也包括通过中枢神经系统,具体地说是脑干内血清素激动剂的作用引起呼吸暂停抑制。实际上,鉴于它们刺激呼吸和上气道运动输出的潜力,最初测试了提高血清素的药物作为睡眠呼吸暂停综合征的药理学疗法。
一个早期的报告提示L-色氨酸-血清素前体可能对睡眠呼吸暂停综合征具有有益的影响[Schmidt,Bull.Eur.Physiol.Respir.,19:625-629(1982)]。新近的氟苯氧丙胺[Hanzel et al.,Chest.,100:416-421(1991)]和帕罗西汀[Kraiczi et al.,Sleep,22:61-67(1999)],都是选择性的血清素再摄取抑制剂(SSRIs),证明了对睡眠呼吸暂停综合征患者有些益处,但不是对所有的患者有益。此外,血清素前体和再摄取抑制剂联合降低了患有睡眠呼吸暂停综合征的英国牛头犬模型中的睡眠呼吸紊乱[Veasey et al.,SleepRes.,A529;1997 and Veasey et al.,Am.J.Resp.Crit.CareMed.,157:A655(1997)]。然而,尽管有正在进行的调查,但是提高血清素的药物的这些鼓舞人的早期结果还未被重复产生出来。
针对提高血清素的药物的前述努力表明血清素前体或SSRIs在呼吸暂停治疗中的潜在效用严格地起因于它们的中枢神经系统作用。因此,恰恰因为SSRIs在外周神经中提高血清素的作用未被检查,所以这些化合物未曾证明在呼吸暂停治疗中具有可重复再现的作用。事实上已经表明刺激呼吸的丁螺环酮-具体的5-羟色胺1A激动剂[Mendelson et al.,Am.Rev.Respir.Dis.,141:1527-1530(1990)]可降低5位睡眠呼吸暂停综合征患者中4位的呼吸暂停指数[Mendelson et al.,J.Clin.Psychopharmacol.,11:71-72(1991)]和消除一个儿童手术后的长吸呼吸[Wilken et al.,J.Pediatr.,130:89-94(1997)。尽管丁螺环酮在全身起作用,但是没有表明外周神经系统中的5-羟色胺受体在呼吸暂停的发生中起作用。丁螺环酮诱发的普通呼吸暂停抑制是并不与外周神经系统中的血清素激活作用对立的中枢神经系统的作用。
使用SSRIs如氟苯氧丙胺或帕罗西汀治疗睡眠呼吸暂停综合征的基本原理部分地起因于它们刺激上气道运动排出的能力。将血清素应用于第四脑室基底[Rose et al.,Resp..Physio.,101:59-69(1995)]或舌下运动核[Kubin et al.,Neurosci.Lett.,139:243-248(1992)]而在猫中产生了上气道运动激活;好象主要是受5-羟色胺2受体介导的作用。相反,给英国牛头犬全身给予5-羟色胺2受体拮抗剂可降低上气道肌肉的电激活,减少上气道的横截面积和促进阻塞性呼吸暂停[Veasey et al.,Am.J.Crit.CareMed.,153:776-786(1996)]。这些观察为在SSRI治疗后,在有些患者中观察到的睡眠呼吸紊乱改善提供了可能的解释。
连同这里提供的资料(实施例2和3)和前述观察,通过全身给予下列可以有效地预防或抑制与睡眠相关的呼吸紊乱(睡眠呼吸暂停综合征、婴儿呼吸暂停、Cheyne-Strokes呼吸、与睡眠相关的通气不足综合征):
(a)显示出血清素2型或3型受体拮抗作用(单独或相互组合)的试剂或试剂的组合,和/或与5-羟色胺1或5-羟色胺2受体拮抗剂组合;
(b)显示出血清素2型和3型受体两个拮抗作用的试剂或试剂的组合,与5-羟色胺1或5-羟色胺2受体激动剂的组合;或
(c)显示出合适的拮抗和激动药理学谱的试剂(即同时作为上面列出的受体亚型的激动剂和拮抗剂的试剂)
优选的实施方案包括下列:
(a)其中血清素激动剂仅仅显示中枢性血清素激活活性的试剂或试剂的组合;
(b)其中血清素激动剂仅仅显示中枢性5-羟色胺2活性的试剂或试剂的组合;
(c)其中血清素拮抗剂仅仅显示外周活性,而血清素激动剂仅仅显示中枢性血清素激活活性的试剂或试剂的组合;
(d)具有诱发中枢神经系统的血清素释放能力并且具有上述讨论的拮抗谱(即5-羟色胺2和5-羟色胺3受体拮抗剂)的试剂或试剂的组合;或
(e)具有诱发中枢神经系统的血清素释放能力并且仅仅具有外周拮抗作用的试剂或试剂的组合;
本领域技术人员将认识到很多血清素受体激动剂,例如但不限于8-OH-DPAT(8-羟基-2-(二正丙基氨基)萘满,舒马曲坦,L694247(2-[5-[3-(4-甲基硫酸氨基)苄基-1,2,4-噁二唑-5-yl]-1H-吲哚-3yl]乙酰胺)、丁螺环酮、alnitidan、zalospirone、伊沙匹降、吉吡隆、佐米曲坦、risatriptan、311C90、α-Me-5-HT、BW723C86(1-[52-噻吩基甲氧基)-1H-3-吲哚基[丙烷-2-胺盐酸盐)、MCPP(间-氯苯基哌嗪),以及可以与血清素受体拮抗剂组合使用以预防或改善与睡眠相关的呼吸紊乱的其它激动剂。
也可以利用除了血清素前体或SSRIs之外的药理学作用机理以提高中枢神经系统的血清素活性。实际上,至少一个机制允许增加的血清素释放以选择性地靶向中枢神经系统。具体地说,位于脑干血清素激活神经元上的突触前α2肾上腺素能受体(异受体)的拮抗作用提高了血清素的释放。已经表明选择性的5-羟色胺2和5-羟色胺3受体拮抗剂阻断突触前α2肾上腺素受体以及突触后5-羟色胺2和5-羟色胺3受体[deBoer,J.Clin.Psychiatr.,57(4):19-25(19960;Devane,J.Clin.Psychiatry.,59(20):85-93(1998);and Puzantian,Am.J.Heatlh-Syst.Pharm.,55:44-49(1998)]。因为这种试剂对中枢性α2受体的亲合力比突触前α2受体高10倍[Puzantian,Am J.Heatlh-Syst.Phare.,55:44-49(1998)],中枢血清素的释放随最小肾上腺素能的副作用,例如高血压而增加。因此由于这些药理学试剂是5-羟色胺2A、5-羟色胺2C和5-羟色胺3受体的高亲合力的拮抗剂,因此净效果是增加脑内的突触后5-羟色胺1的活性和降低中枢和外周神经系统中5-羟色胺2和5-羟色胺3受体的突触后活性。这些药理作用中的每一个都足以刺激呼吸和抑制呼吸暂停。
因此,鉴于前述观察,通过全身给予具有α2肾上腺素能拮抗剂活性和血清素2型或3型受体拮抗活性的药理学试剂或试剂的组合(单独或相互组合),也可以有效地预防或抑制与睡眠相关的呼吸紊乱(睡眠呼吸暂停综合征、婴儿呼吸暂停、Cheyne-Strokes呼吸、与睡眠相关的通气不足综合征)。优选的实施方案包括:
(a)其中α2肾上腺素能拮抗剂作用在中枢发挥的试剂或试剂的组合;
(b)其中血清素拮抗剂作用在外周发挥的试剂或试剂的组合;
(c)其中α2肾上腺素能拮抗剂作用在中枢发挥和血清素拮抗剂作用在外周发挥的试剂或试剂的组合;
(d)实施方案a-c的试剂或试剂的组合,其中α2肾上腺素能拮抗剂作用在突触前发挥;
(e)实施方案a-d的试剂或试剂的组合,其中α2肾上腺素能拮抗剂作用选择性地在血清素激活的神经元上的突触前异受体处发挥;或
(f)实施方案a-d的试剂或试剂的组合,其中α2肾上腺素能拮抗剂作用通过具有下列药理学谱的试剂或试剂的组合来发挥:α2肾上腺素能拮抗剂活性伴有血清素2或3型受体拮抗剂活性。
本领域技术人员将认识到很多α2肾上腺素能受体拮抗剂,例如但不限于苯氧基苄胺、酚妥拉明、妥拉苏林、特拉唑嗪、多沙唑嗪、三甲氧唑啉、育亨宾、吲哚哌胺、ARC239、哌唑嗪以及可以与血清素受体拮抗剂组合使用以预防或改善睡眠相关呼吸紊乱的其它拮抗剂。
给诊断患有与睡眠相关的呼吸紊乱的个体施用预防或抑制这种紊乱的有效量的具有任何前述药理学谱的组合物或试剂。具体剂量可以根据因素例如体重或体表面积进行计算。确定治疗与睡眠相关的呼吸紊乱的合适剂量所需的更多精确计算由本领域普通技术人员按常规方式进行,无需过多实验。通过使用确定剂量建立的试验可以确定合适的剂量。前述方法的给药途径可以通过任何全身方法,包括口腔、腹腔内、皮下、静脉内、肌内、经皮,或通过其它给药途径。也可以使用渗透小泵和定时释放的小丸或其它给药储库形式。
最后,本领域技术人员将认识到关于上述讨论的化合物,这种化合物可以含有手性中心。因此这种试剂可以作为不同的对映体或对映体混合物存在。本发明包括单独使用任何一个对映体或含有一个或多个立体异构体的对映体混合物内含有的对映体。
尽管已经通过优选实施方案描述了本发明,但是意图是本发明包括本领域技术人员考虑这里的公开内容所想到的所有改变和变型,尤其是权利要求及其需要条件的最宽泛的适当解释内的那些实施方案。这里引用的所有文献引入作为参考。
Claims (16)
1.一种预防或改善与睡眠相关的呼吸紊乱的方法,包括给需要它的患者施用有效量的至少一种游离碱或季铵化形式的血清素受体拮抗剂,该拮抗剂选自zatosetron、曲匹西隆、多拉司琼、氢化多拉司琼、仙人球毒碱、苯呋噁庚胺、高氯环、哌拉平、克塞平、奥氮平、氯丙嗪、氟哌啶醇、r(+)奥丹西隆、西沙比得、norcisapride、(+)西沙比得、(-)西沙比得、(+)norcisapride、(-)norcisapride、去甲奥氮平、2-羟甲基奥氮平和1-(2-氟苯)-3-(4-羟氨基乙基)-丙-2-烯-1-酮-O-(2-二甲基氨乙基)-肟。
2.权利要求1的方法,其中与睡眠相关的呼吸紊乱选自阻塞性睡眠呼吸暂停综合征、早熟性呼吸暂停、先天性中枢性通气不足综合征、肥胖性通气不足综合征、中枢性睡眠呼吸暂停综合征、Cheyne-Strokes呼吸和打鼾。
3.一种预防或改善与睡眠相关的呼吸紊乱的方法,包括给需要它的患者施用有效量的至少一种季铵化形式的血清素受体拮抗剂,该拮抗剂选自奥丹西隆、酮色林、利司哌酮、塞庚啶、氯氮平、甲基麦角新酯、格雷西龙、米塞林、利坦色林、肉桂硫胺、LY-53,857、麦角苄酯、LY-278,584、美赛西平、p-NPPL、NAN-190、哌嗪、SB-206553、SDZ-205,557、3-托烷基-吲哚-3-羧酸酯和3-托烷基-吲哚-3-羧酸酯甲碘化物。
4.权利要求3的方法,其中与睡眠相关的呼吸紊乱选自阻塞性睡眠呼吸暂停综合征、早熟性呼吸暂停、先天性中枢性通气不足综合征、肥胖性通气不足综合征、中枢性睡眠呼吸暂停综合征、Cheyne-Strokes呼吸和打鼾组成的组。
5.一种预防或改善与睡眠相关的呼吸紊乱的方法,包括给需要它的患者施用有效量的
(a)至少一种血清素受体拮抗剂
(i)的游离碱或季铵化形式,选自zatosetron、曲匹西隆、多拉司琼、氢化多拉司琼、仙人球毒碱、苯呋噁庚胺、高氯环、哌拉平、克塞平、奥氮平、氯丙嗪、氟哌啶醇、r(+)奥丹西隆、西沙比得、norcisapride、(+)西沙比得、(-)西沙比得、(+)norcisapride、(-)norcisapride、去甲奥氮平、2-羟甲基奥氮平和1-(2-氟苯)-3-(4-羟氨乙基)-丙-2-烯-1-酮-O-(2-二甲基氨乙基)-肟。
(ii)的季铵化形式,选自奥丹西隆、酮色林、利司哌酮、塞庚啶、氯氮平、甲基麦角新酯、格雷西龙、米塞林、利坦色林、肉桂硫胺、LY-53,857、麦角苄酯、LY-278,584、美赛西平、p-NPPL、NAN-190、哌嗪、SB-206553、SDZ-205,557、3-托烷基-吲哚-3-羧酸酯和3-托烷基-吲哚-3-羧酸酯甲碘化物;和
(iii)其混合物;和
(b)血清素受体激动剂。
6.权利要求5的方法,其中季铵化形式的血清素受体拮抗剂是甲基化、乙基化或苄基化的。
7.权利要求5的方法,其中血清素受体激动剂选自8-OH-DPAT、舒马曲坦、L694247(2-[5-[3-(4-甲基硫酸氨基)苄基-1,2,4-噁二唑-5-yl]-1H-吲哚-3-基]乙酰胺)、丁螺环酮、alnitidan、zalospirone、伊沙匹降、吉吡隆、佐米曲坦、risatriptan、311C90、α-Me-5-羟色胺、BW723C86和MCPP。
8.权利要求5的方法,其中血清素受体激动剂是5-羟色胺1受体亚型激动剂。
9.权利要求5的方法,其中血清素受体激动剂是5-羟色胺2受体亚型激动剂。
10.权利要求5的方法,其中血清素受体激动剂的作用在中枢神经系统中发挥。
11.权利要求5的方法,其中血清素受体拮抗剂的作用在外周神经系统中发挥。
12.权利要求5的方法,其中血清素受体激动剂的作用在中枢神经系统发挥并且其中血清素受体拮抗剂的作用在外周神经系统发挥。
13.一种预防或改善与睡眠相关的呼吸紊乱的方法,包括给需要它的患者施用有效量的
(a)至少一种血清素受体拮抗剂
(i)的游离碱或季铵化形式,选自zatosetron、曲匹西隆、多拉司琼、氢化多拉司琼、仙人球毒碱、苯呋噁庚胺、高氯环、哌拉平、克塞平、奥氮平、氯丙嗪、氟哌啶醇、r(+)奥丹西隆、西沙比得、norcisapride、(+)西沙比得、(-)西沙比得、(+)norcisapride、(-)norcisapride、去甲奥氮平、2-羟甲基奥氮平和1-(2-氟苯)-3-(4-羟氨基乙基)-丙-2-烯-1-酮-O-(2-二甲基氨基乙基)-肟。
(ii)的季铵化形式,选自奥丹西隆、酮色林、利司哌酮、塞庚啶、氯氮平、甲基麦角新酯、格雷西龙、米塞林、利坦色林、肉桂硫胺、LY-53,857、麦角苄酯、LY-278,584、美赛西平、p-NPPL、NAN-190、哌嗪、SB-206553、SDZ-205,557、3-托烷基-吲哚-3-羧酸酯和3-托烷基-吲哚-3-羧酸酯甲碘化物;和
(iii)其混合物;和
(b)有效量的选择性的血清素再摄取抑制剂。
14.权利要求13的方法,其中选择性的血清素再摄取抑制剂选自氟苯氧丙胺和帕罗西汀组成的组。
15.权利要求13的方法,其中选择性血清素再摄取抑制剂选自三氟戊肟胺、舍曲林、西酞普兰、去甲氟西汀、r(-)氟苯氧丙胺、s(+)氟苯氧丙胺、脱甲基舍曲林、脱甲基西酞普兰、文拉法新、milnacipran、西布曲明、奈法唑酮、R-羟基奈法唑酮、(-)文拉法新和(+)文拉法新组成的组。
16.一种预防或改善睡眠相关呼吸紊乱的方法,包括给需要它的患者施用
(a)有效量的至少一种血清素受体拮抗剂,选自zatosetron、曲匹西隆、多拉司琼、氢化多拉司琼、仙人球毒碱、苯呋噁庚胺、高氯环、哌拉平、奥丹西隆(GR38032F)、酮色林、克塞平、奥氮平、氯丙嗪、氟哌啶醇、r(+)奥丹西隆、西沙比得、norcisapride、(+)西沙比得、(-)西沙比得、(+)norcisapride、(-)norcisapride、desmethyl奥氮平、2-羟甲基奥氮平、1-(2-氟苯)-3-(4-羟氨基乙基)-丙-2-烯-1-酮-O-(2-二甲基氨基乙基)-肟、利司哌酮、塞庚啶、氯氮平、甲基麦角新酯、格雷西龙、米塞林、利坦色林、肉桂硫胺、LY-53,857、麦角苄酯、LY-278,584、美赛西平、p-NPPL、NAN-190、哌嗪、SB-206553、SDZ-205,557、3-托烷基-吲哚-3-羧酸酯和3-托烷基-吲哚3-羧酸酯甲碘化物;和
(b)至少一种选择性的血清素再摄取抑制剂,选自三氟戊肟胺、舍曲林、氟苯氧丙胺、帕罗西汀、西酞普兰、去甲氟西汀、r(-)氟苯氧丙胺、s(+)氟苯氧丙胺、脱甲基舍曲林、脱甲基西酞普兰、文拉法新、milnacipran、西布曲明、奈法唑酮、R-羟基奈法唑酮、(-)文拉法新和(+)文拉法新。
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