CN102458400A - 用于治疗病灶性前庭功能障碍的血清素5-ht3受体拮抗剂 - Google Patents
用于治疗病灶性前庭功能障碍的血清素5-ht3受体拮抗剂 Download PDFInfo
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- CN102458400A CN102458400A CN2010800328641A CN201080032864A CN102458400A CN 102458400 A CN102458400 A CN 102458400A CN 2010800328641 A CN2010800328641 A CN 2010800328641A CN 201080032864 A CN201080032864 A CN 201080032864A CN 102458400 A CN102458400 A CN 102458400A
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- ondansetron
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Abstract
本发明涉及用于治疗病灶性前庭功能障碍的血清素5-HT3受体拮抗剂或血清素5-HT3受体基因表达的抑制剂。
Description
技术领域
本发明涉及用于治疗或预防病灶性前庭功能障碍的血清素5-HT3受体拮抗剂或血清素5-HT3受体基因表达的抑制剂。
背景技术
前庭功能障碍的介绍
前庭(内耳)功能障碍可以导致头晕、眩晕、失衡、听力改变、恶心、疲劳、焦虑、注意力难以集中、和其他症状,潜在地对人每天的功能,工作能力,与家庭和朋友的关系以及生活质量有破坏性的影响。
例如,前庭神经炎是非神经性眩晕的首要住院病因。由于其病因学在很大程度上是未知的,流行病学研究依据来源而变化(据信其发病率为每年100000个人中3.5至50个新发病例)。过去,前庭神经的炎症或迷路缺血被提议作为前庭神经炎的病因。目前,倾向于病毒的原因。1型单纯疱疹病毒的再激活将解释在这种情况下眩晕危象的反复发作。
前庭功能障碍还可能与老年人的大多数跌倒有关并且其预防成为了首要任务。事实上老年人跌倒占法国健康保险总预算的1%以上(INSEE 1990)。其在法国影响30%的65岁以上的人和50%的80岁以上的人。老年人跌倒与2/3的65岁以上由意外导致的死亡有关,并且在随后的时间死亡风险增加4倍。
前庭功能障碍的病因学
尽管前庭功能障碍的病因学基本上未知,但广泛认可的是前庭功能障碍(也称为前庭缺陷)构成了一个巨大家族的与前庭器官相关的病况。这些功能障碍可以通过它们的推定来源来区分,由此可以鉴别(1)病灶性前庭功能障碍和(2)非病灶性前庭功能障碍。
1)病灶性前庭功能障碍是指这样的前庭功能障碍,其中存在内耳细胞和/或前庭神经的病变或在功能障碍时程期间将出现内耳细胞和/或前庭神经的病变。在此情况下,前庭功能性受损,因为使用临床功能测试(VOR,VNG)可以观察到这种受损。病灶性前庭功能障碍包括:
-其中感染累及内耳和/或前庭神经,诱发可逆的和/或不可逆的损害的前庭功能障碍。此组病况的一个实例是前庭神经炎。
-其中内耳液水平受影响(内淋巴的数量、组成和/或压力异常)的前庭功能障碍,这些功能障碍通常在疾病时程期间发展成病变。此组病况的实例是梅尼埃病和继发性内淋巴积液。目前它们与耳鸣和听力损失有关。
-由前庭终器的损伤或病变诱发的前庭功能障碍。所述病况的实例是由局部缺血、兴奋性中毒、影响颞骨的创伤导致的眩晕。
2)非病灶性前庭功能障碍是指由短暂和频繁的反复眩晕危象所支撑的前庭功能障碍,其中观察不到内耳细胞和/或前庭神经的病变。在此情况下,使用功能测试(VOR,VNG)评价的眩晕危象前庭功能性与健康前庭没有差别。非病灶性前庭功能障碍包括:
-其中在部分内耳内收集到碎屑的前庭功能障碍,。这种碎屑称为耳石,由小的碳酸钙晶体组成并且当它们移动时,它们向大脑发出假信号。所述病况的实例是体位性眩晕。
-无耳鸣或听力损失的未知原因的反复前庭功能障碍。
前庭功能性损失的评价
在人类中,前庭终器的形态功能改变不能直接评价(除了可以通过IRM检测到的大病灶以外)。目前使用间接的评价方法来评价前庭的功能损失。这些行为测试方法通常在ENT诊所/医院处进行。这当中,我们可以提到前庭眼震电图(vestibulonystagmography)(VNG),使用热或旋转试验对前庭眼动反射(VOR)的评价。
前庭缺陷的治疗
目前对前庭缺陷的治疗主要集中在使用前庭麻痹药物来减少眩晕危象,同时通过使用止吐药物限制植物性神经系统反应。以前庭神经炎(推定由细菌或病毒感染所引起)为例,皮质类固醇和抗病毒药物是试图限制前庭损害扩大的仅有的治疗药物。在大多数前庭缺陷中,鉴于缺少病因学,它们的作用仍处于争论当中。例如,前庭神经炎后的康复通常是不完全的。在对60名患者的研究中,在症状发作后1个月在大约90%患者中发现了水平半规管轻瘫,并且在6个月后80%患者中发现水平半规管轻瘫;仅在42%的患者中冷热反应正常。基于此病况的发病率,在美国每年大约4000人发生不能通过其他机制来代偿的实质性和永久性前庭眼动反射单侧动态缺陷。此缺陷导致视力受损和步行过程中并且尤其是在头朝向受累耳侧移动过程中的体位失衡。
因此,需要防止、减少或治疗病灶性前庭功能障碍的发病率和/或严重性的保护性或修复治疗,内耳细胞和/或前庭神经的所述功能改变是由于不同来源的炎症、病变或损伤引起的。
本发明人惊奇地发现,血清素5-HT3受体拮抗剂诸如奥丹西隆能够通过保护内耳细胞和前庭神经免受损害或变性来预防或治疗前庭病变。从Jellish等(Journal of Clinical Anesthesia 2007,9:451-456),已知奥丹西隆用于减少中耳外科治疗后的手术后恶心或呕吐。从Rice等(The Lancet 1995,345:1182-1183)还已知奥丹西隆用于治疗脑干疾病诸如多发性硬化中的症状,例如眩晕、恶心和呕吐。最后,从US2007265329还已知奥丹西隆用于预防由化疗诱发的恶心和呕吐。已经报道奥丹西隆的止吐特性是由对位于呕吐中枢(脑干外侧网状结构)的5-HT3血清素受体的拮抗作用所介导,该呕吐中枢接纳前庭传入神经、躯体传入神经、内脏传入神经和边缘传入神经(Tyers MB,Freeman AJ.Oncology,1992,49:263-268)。此药理学作用阻止了通常由血清素介导的呕吐反射。
尽管奥丹西隆用于治疗或预防与眩晕相关的呕吐症状,但本发明人发现其还能够预防和/或治疗前庭器官内的直接损伤或病变。
发明内容
本发明涉及用于治疗病灶性前庭功能障碍的血清素5-HT3受体拮抗剂或血清素5-HT3受体基因表达抑制剂。
附图说明
图1:图示在20名患者的样本中奥丹西隆与甲氧氯普胺相对比的临床作用。图示在20名患者的样本中用奥丹西隆(8mg/j,n=10)与甲氧氯普胺(30mg/j,n=10)相对比治疗5天的临床效应。两种分子与前庭麻痹剂(vestibuloplegics)、皮质类固醇和抗病毒药物一起施用于怀疑有前庭神经炎的患者。在治疗(5天持续时间)后48h和1个月使用前庭眼震电图评估前庭缺陷的发展(A)。在早期冷热测试时,在用奥丹西隆治疗的患者中,与甲氧氯普胺相比前庭缺陷不太显著(56.53%对84.38%,p=0.03)。1月后,在我们的样本中差异不显著(43.0%奥丹西隆对63.4%甲氧氯普胺,p=0.07)。在用奥丹西隆给药的患者中首次行走的时间(B)和住院时间(C)也显著减少。
图2:5HT-3受体在哺乳动物前庭中的表达。(A)在斯卡尔帕神经节(A)和前庭感觉上皮(B-D)中5HT-3A受体的免疫细胞学检测。在A中,注意到施旺细胞和内皮细胞没有被标记。在B-D中,注意到感觉上皮周围的移行细胞(大箭头)和在少数神经纤维(箭头)中特异性地表达5HT-3A受体。
图3:关于奥丹西隆对兴奋性毒性(红藻氨酸盐)-诱发的前庭缺陷的作用的行为评价。(A)用来诱发单侧病灶性前庭缺陷的试验方案。奥丹西隆以4mg/kg经腹膜内注射(ip)。KA注射后1h,测试动物的前庭行为,然后在治疗组中注射奥丹西隆。对照动物不接受奥丹西隆注射。随后,在KA注射后2h、6h、24h和48h时测试动物。(B)红藻氨酸盐诱发的前庭缺陷的行为表达。在经鼓膜注射红藻氨酸后,大鼠显示强烈的兴奋性毒性诱发的前庭缺陷,该前庭缺陷在48小时内逐渐减弱。当动物用奥丹西隆治疗时这种前庭缺陷减弱的时程发生改变,在24小时时前庭缺陷显著减弱(*p=0.022;曼-怀二氏检验;n≥8)。随后,由于内源性代偿机制,治疗的和未治疗的动物恢复至类似的前庭缺陷水平。
图4:兴奋性毒性(红藻氨酸盐)-诱发的前庭病变的组织学评价。在KA经鼓膜注射后2小时,其诱发感觉上皮中前庭传入神经的大的细胞外病灶(A),而对侧耳无病变(C)。观察到沿毛细胞有大的肿胀的突触末梢,而不是典型的I型神经盏(calyceal)和II型神经终扣(bouton)末梢。此病变后24小时,对于使用奥丹西隆(B)和不使用奥丹西隆(D)观察到新的神经盏和神经终扣型末梢。
图5:兴奋性毒性(红藻氨酸盐)-诱发的前庭病变的形态计量分析。经鼓膜注射KA没有诱发毛细胞或支持细胞的损失。相反,确定的周围有神经盏的I型毛细胞的数量被KA极大地和显著地减少(P<0.001),这通过未被确定的毛细胞数量的增加证实(P<0.01)。当在细胞外损伤后24小时计数时,刚确定的I型毛细胞的数量显著增加(p<0.01),但未确定的毛细胞的数量没有显著减少。对于奥丹西隆治疗,我们观察到在KA病变后24小时I型毛细胞数量的显著增加(p<0.01)。奥丹西隆治疗显著地减少未确定的毛细胞的数量(P<0.01)。
图6:关于奥丹西隆对双侧(腈)-诱发的前庭缺陷的作用的行为评价。(A)用来诱发双侧病灶性前庭缺陷的试验方案。(B-E)在奥丹西隆治疗或缺少奥丹西隆治疗时前庭缺陷表达的时程。当动物在注射IDPN后同时(B)、24h(C)或48h(D)接受奥丹西隆时增加的前庭缺陷没有显著地改变。相反,当在诱发前庭缺陷后24小时和48小时注射奥丹西隆(E)时,增加的前庭缺陷的时程发生显著变化(p=0.029)。
具体实施方式
由发明人最近进行的一项临床研究证明,血清素5-HT3受体拮抗剂(即1,2,3,9-四氢-9-甲基-3-[(2-甲基-1H-咪唑-1-基)甲基]-4H-咔唑-4-酮,也称为奥丹西隆)对伴有前庭神经炎的前庭损害具有适宜的康复作用。此血清素5-HT3受体拮抗剂有效地减少前庭终器的功能改变以及随后在此内耳病理学条件下所遭遇的前庭缺陷。此结果是杰出的,因为其首次证明了集中于保护和/或恢复前庭功能性的药理学治疗可以带来具体的解决方案从而挽救病灶性前庭损害后的前庭功能性。其也提供了开发针对病灶性前庭缺陷的首个治愈性治疗的独一无二的机会。
另外,发明人首次观察到血清素5-HT3受体蛋白在前庭的几个部位中表达。
因此,本发明提供了用于治疗病灶性前庭功能障碍的方法和组合物(例如药物组合物)。
如本文所使用如本文所使用,术语“治疗(treating)”、“治疗(treatment)”和“疗法(therapy)”是指治愈性治疗。因此,本发明的目的是提供前庭功能障碍的永久终结或通过恢复前庭终器的功能性或部分功能性并且因此恢复前庭功能性来改善受试者的病况。本发明没有提供用于控制与前庭缺陷有关的不良症状诸如呕吐和恶心的方法,但提供了治愈前庭缺陷的方法。本发明还着眼于预防任何病灶出现或预防已经存在的病变增大。
本发明提供了在用于保护/恢复患有病灶性前庭功能障碍的受试者的前庭神经元网络并且因此用于保护/恢复前庭功能性的方法中使用的方法和组合物(诸如药物组合物)。
如本文所使用,术语″病灶性前庭功能障碍或缺陷″是指这样的前庭功能障碍,其中存在内耳细胞和/或前庭神经的病变或在功能障碍时程期间将出现内耳细胞和/或前庭神经的病变。在此情况下,前庭功能性受损。病灶性前庭功能障碍包括:
-其中感染累及内耳和/或前庭神经,诱发可逆的和/或不可逆的损害的前庭功能障碍。此组病况的一个实例是前庭神经炎。
-其中内耳液水平受影响(内淋巴的数量、组成和/或压力异常)的前庭功能障碍,这些功能障碍通常在疾病时程期间发展成病变。此组病况的实例是梅尼埃病和继发性内淋巴积液。
-由前庭终器的损伤或病变诱发的前庭功能障碍。所述病况的实例是由局部缺血、兴奋性中毒、影响颞骨的创伤导致的眩晕。
本发明考虑的病灶性前庭功能障碍的实例包括但不限于前庭神经炎、病毒性神经炎、迷路炎、病毒性内淋巴迷路炎、药物造成的耳毒性、梅尼埃病、内淋巴积液、带有病灶性前庭缺陷的头部创伤、迷路出血、慢性或急性迷路感染、浆液性迷路炎(serous labyrinthine)、气压创伤、自身免疫性内耳疾病、老年性前庭症(presbyvestibulia),、中毒性前庭损害。
根据本发明,病灶性前庭功能障碍可以使用鉴别大病灶的IRM或通过评价前庭功能性损失的间接评估方法鉴定。这些方法通常在ENT诊所/医院处进行并且包括前庭眼震电图(VNG),使用冷热或旋转试验对前庭眼动反射(VOR)的评估。前庭-眼动反射(VOR)的功能是稳定位移过程中视网膜上的视觉影像。此VOR测量提供了研究前庭系统功能性的便利方法。基本上,范例基于通过红外光投影技术监测眼球移动(Fetoni等,2003,Hearing Research 2003,182:56-64)。患者在黑暗中围绕其垂直轴和纵轴正弦式摆动以便诱发水平和垂直方向的眼球反应。前庭的任何功能性损害均与诱发的VNG的增益改变有关。除VOR和VNG之外,姿势描记法用来检测也与前庭的损害有关的身体姿势偏斜。形态功能研究诸如功能成像(IRM或CAT(计算机轴位体层摄影)和衍生技术)可以用来检测前庭终器内的复杂病灶。专门设计的VNG、VOR和姿势测试在前庭缺陷的动物模型中用于评价前庭中损伤或病灶的程度。也可以使用常规的光学或电子显微镜对固定的组织(前庭神经节和前庭终器)进行组织学研究。这些研究大多数在啮齿动物中进行。
如本文所使用,术语“受试者”表示哺乳动物,诸如啮齿动物、猫科动物、犬科动物和灵长类。优选地,根据本发明的受试者是人。
根据一个方面,本发明涉及用于治疗病灶性前庭功能障碍的血清素5-HT3受体拮抗剂。
根据另一个方面,本发明涉及在用于恢复患有病灶性前庭功能障碍的受试者的前庭功能性的方法中使用的血清素5-HT3受体拮抗剂。所述恢复可以使用如本文上面提及的VNG或VOR评估进行评价。
如本文所使用,术语″血清素5-HT3受体″具有它在本领域中的普通含义,并且是指5-羟色胺(血清素)受体亚型3。该术语可以包括天然存在的血清素5-HT3受体和其变体和修饰形式。血清素5-HT3受体可以来自任何来源,但又代表性地是哺乳动物(例如,人和非人灵长类)血清素5-HT3受体,特别是人血清素5-HT3受体。
如本文所使用,术语″血清素5-HT3受体拮抗剂″包括任何化学实体,在施用于患者时其导致患者中与血清素5-HT3受体的活化相关的生物活性的抑制或下调,所述生物活性包括其它源于血清素5-HT3受体与其天然配体(即,血清素)结合引起的任何下游生物效应。此种血清素5-HT3受体拮抗剂包括可以阻断血清素5-HT3受体活化或血清素5-HT3受体活化的任何下游生物效应的任何试剂。例如,此种血清素5-HT3受体拮抗剂可以通过占用血清素5-HT3受体的配体结合位点或其部分来发挥作用,从而使所述受体不能接近其天然配体,以致于其正常生物活性被阻止或降低。化合物针对血清素5-HT3受体的拮抗活性可以通过使用本领域中众所周知的多种方法确定。例如,5-HT3拮抗活性可以在放射性配体结合测定中和大鼠中5-HT-诱发的von Bezold-Jarisch反射中评价,诸如Turconi M.等.(1990)所述,该文献通过参考并入本文通过参考并入本文。
在一个实施方案中,血清素5-HT3受体拮抗剂可以是有机小分子。
术语“有机小分子”是指与通常在药物中使用的那些有机分子的大小相当的分子。该术语不包括生物大分子(例如蛋白质、核酸等)。优选的有机小分子的大小范围为一直到约5000Da,更优选一直到2000Da,并且最优选一直到约1000Da。
本发明考虑的示例性血清素5-HT3拮抗剂包括但不限于美国专利号4,695,578;4,906,755;4,886,808;5,677,326;5,202,333;5,225,407;5,360,800;6,770,655;;;;;;;UK专利申请号2100259,2125398,2153821,2160871和2202530,,,;公布的欧洲专利申请号94724,99789,200444,242973,247266,266730,302699,306323,307172,309423,313393,337547,339950,353983,356098,358903,381422,397364和397365,,,,,,,,,,,,,,,,,;以及PCT专利申请号88/01866中所述的有机小分子,这些文献通过参考并入本文。
根据具体的实施方案,根据本发明使用的血清素5-HT3受体拮抗剂可以是式(I)的化合物和其生理学可接受的盐、游离酸形式、游离碱形式和溶剂化物(例如水合物):
其中R1表示C3-7环烷基-(C1-4)烷基或C3-10炔基;且由R2、R3和R4表示的基团之一是氢原子或C1-6烷基、C3-7环烷基、C2-6烯基或苯基-(C1-3)烷基且其他两个基团中的每一个可以相同或不同,表示氢原子或C1-6烷基。
式(I)的化合物记载在欧洲专利号19156和美国专利号4,695,578中,这些专利通过参考并入本公开中。
当通式(I)中的基团R1表示C3-7环烷基-(C1-4)烷基时,C3-7环烷基部分可以是例如环丙基、环丁基、环戊基、环己基或环庚基;且C1-4烷基部分可以是甲基、乙基、丙基、丙-2-基或丁基。基团R1因此可以表示,例如环丙基甲基、环己基丙基或环庚基甲基。当环烷基环包含5、6或7个碳原子时,其可以任选地包含一个或两个双键。这种基团的实例包括环己烯基和环己二烯基。
当R1表示C3-10炔基时,其可以是,例如,2-丙炔基或2-辛炔基。应该理解当R表示C3-10炔基时,三键可以不邻接氮原子。
关于通式(I)中由R2、R3和R4表示的基团,烷基可以是直链或支链烷基,例如,甲基、乙基、丙基或丙-2-基;烯基可以是,例如,丙烯基;苯基-(C1-3)烷基可以是,例如,苄基、苯乙基或3-苯基丙基;且环烷基可以是,例如,环戊基、环己基或环庚基。
应当理解,四氢咔唑酮环3-位上的碳原子是不对称的并且可以存在于R-或S-构型中。此外,应当理解,取决于基团R1、R2、R3和R4的性质,同分异构中心可以在分子的其他地方出现。本发明包括式(I)化合物的所有个别异构形式和它们的所有混合物。
在优选的实施方案中,本发明包括式(I)化合物的光学纯R(+)异构体的用途。
通式(I)化合物的合适的生理学可接受盐包括与有机酸或无机酸形成的酸加成盐,例如,盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、柠檬酸盐、延胡索酸盐和马来酸盐。溶剂化物可以是,例如,水合物。
通式(I)表示的化合物的优选类型是这样的化合物,其中由R2、R3和R4表示的基团之一表示C1-3烷基或C3-6烯基且其他两个基团中的每一个可以相同或不同,表示氢原子或C1-3烷基。当R2表示氢原子时,R3和/或R4优选地表示C1-3烷基。当R2表示C1-3烷基时,R3和R4两者优选地表示氢原子。
优选的式(I)化合物可以是1,2,3,9-四氢-3-[(2-甲基-1H-咪唑-1-基)甲基]-9-(丙-2-烯基)-4H-咔唑-4-酮;9-环戊基-1,2,3,9-四氢-3-[(2-甲基-1H-咪唑-1-基)甲基]-4H-咔唑-4-酮;和1,2,3,9-四氢-3-[2-甲基-1H-咪唑-1-基)甲基]-9-(丙-2-基)-4H-咔唑-4-酮以及它们的生理学可接受的盐和溶剂化物。
根据本发明使用的特别合适的血清素5-HT3拮抗剂是奥丹西隆和其生理学可接受的盐、游离酸形式、游离碱形式和溶剂化物(例如水合物),奥丹西隆是1,2,3,9-四氢-9-甲基-3-[(2-甲基-1H-咪唑-1-基)甲基]-4H-咔唑-4-酮的批准名称,该化合物可由下式表示:
根据本发明使用的其他特别合适的血清素5-HT3拮抗剂可以选自:帕洛诺司琼(palonosetron)、托烷司琼、来立司琼(lerisetron)、阿洛司琼、格雷西隆、多拉司琼、贝美噻通、雷莫司琼、阿扎西隆、伊他司琼(itasetron)、扎考必利和西兰司琼。
帕洛诺司琼是(3aS)-2-[(S)-1-氮杂双环[2.2.2]辛-3-基]-2,3,3a,4,5,6-六氢-1-氧代-1H苯并[de]异喹啉并且记载在美国专利号5,202,333中。
托烷司琼是(+-)1H-吲哚-3-羧酸(3-内)-8-甲基-8-氮杂双环[3.2.1]辛-3-基-酯并且记载在美国专利号4,789,673中。
来立司琼是(1-(苯基甲基)-2-(1-哌嗪基)-1H-苯并咪唑)并且记载在美国专利号5,256,665中。
阿洛司琼是2,3,4,5-四氢-5-甲基-2-[(5-甲基-1H-咪唑-4-基)甲基]-1H-吡啶并[4,3-b]吲哚-1-酮并且记载在美国专利号5,360,800中。
格雷西隆是内-N-(9-甲基-9-氮杂双环[3.3.1]壬-3-基)-1-甲基-1H-吲唑-3-甲酰胺并且记载在美国专利号4,886,808中。
多拉司琼是(2[α],6[α],8[α],9[α][β])-八氢-3-氧代-2,6-亚甲基-2H-喹嗪-8-基-1H-吲哚-3-羧酸酯,并且记载在美国专利号4,906,755中。
雷莫司琼是(-)-(R)-5-[(1-甲基-1H-吲哚-3-基)羰基]-4,5,6,7-四氢-1H-并且记载在欧洲专利申请号381422A1中。
阿扎西隆是N-1-氮杂双环[2.2.2]辛-3-基-6-氯-3,4-二氢-4-甲基-3-氧代-2H-1,4-苯并嗪-8-甲酰胺盐酸盐。
伊他司琼是(3-α-托品基)1H-苯并咪唑酮-3-甲酰胺盐酸盐。
扎考必利是4-氨基-N-(1-氮杂双环[2.2.2]辛-3-基)-5-氯-2-甲氧基苯甲酰胺并且记载在欧洲专利申请号099789A1中。
西兰司琼是R-(-)5,6,9,10-四氢-10-[(2-甲基-咪唑-1-基)甲基]-4H-吡啶并[3.2.1-jk]咔唑-11(8H)-酮,并且记载在美国专利号4,939,136中。
在另一个实施方案中,根据本发明使用的血清素5-HT3受体拮抗剂可以包括可以阻断血清素5-HT3受体活化的抗体(该术语包括抗体片段)。
具体地,血清素5-HT3受体拮抗剂可以包括针对血清素5-HT3受体或血清素5-HT3受体配体的抗体,使得所述抗体削弱配体与所述受体的结合。
针对血清素5-HT3受体的抗体可以根据已知的方法通过向选自例如,尤其是,猪、牛、马、兔、山羊、绵羊、和小鼠的宿主动物施用适宜抗原或表位产生。本领域中已知的多种佐剂可以用来增强抗体的产生。尽管可用于实施本发明的抗体可以是多克隆的,但优选单克隆抗体。针对血清素5-HT3受体或血清素5-HT3受体的配体的单克隆抗体可以使用通过培养的连续细胞系产生抗体分子的任何技术制备和分离。用于生产和分离的技术包括但不限于最初由Kohler和Milstein(1975)所述的杂交瘤技术;人B-细胞杂交瘤技术(Cote等,1983);和EBV-杂交瘤技术(Cole等,1985)。备选地,记载用于产生单链抗体的技术(参见,例如,美国专利号4,946,778)可以采用以产生抗-5-HT3或抗-5-HT3配体的单链抗体。可用于实施本发明的血清素5-HT3受体拮抗剂还包括抗-5-HT3或抗-5-HT3配体的抗体片段,包括但不限于F(ab′)2片段,其可以通过将完整抗体分子以胃蛋白酶消化产生;和Fab片段,其可以通过将F(ab′)2片段的二硫键还原产生。备选地,可以构建Fab和/或scFv表达文库从而允许快速鉴定对血清素5-HT3受体具有所需特异性的片段。
人源化抗-血清素5-HT3受体或抗-5-HT3配体的抗体和它们的抗体片段也可以根据已知技术来制备。“人源化抗体”是包含来源于非人免疫球蛋白的最少序列的非人(例如,啮齿动物)嵌合抗体的形式。对于大多数部分,人源化抗体是人免疫球蛋白(受者抗体),其中来自受者的超变区(CDR)的残基被来自具有所需特异性、亲和性和能力的非人物种(供体抗体)的超变区的残基替换,所述非人物种诸如小鼠、大鼠、兔或非人灵长类。在一些情况下,人免疫球蛋白的构架区(FR)残基被相应的非人残基替换。此外,人源化抗体可以包含在受者抗体或供体抗体中不存在的残基。作出这些修饰以进一步改进抗体性能。通常,人源化抗体将包含至少一个且有代表性地两个可变结构域的基本上全部结构域,其中所有或基本上所有超变环与非人免疫球蛋白的那些相对应,且所有或基本上所有的FR是人免疫球蛋白序列的那些。人源化抗体任选地还将包含免疫球蛋白恒定区(Fc)的至少一部分,有代表性地是人免疫球蛋白的免疫球蛋白恒定区(Fc)的至少一部分。制备人源化抗体的方法记载在例如Winter(美国专利号5,225,539)和Boss(Celltech,美国专利号4,816,397)中。
在如上所述产生针对血清素5-HT3受体的抗体后,本领域技术人员可以容易地选择阻断血清素5-HT3受体活化的那些。
在另一个实施方案中,根据本发明使用的血清素5-HT3受体拮抗剂是适体。适体是一类分子,该类分子就分子识别而言代表着抗体的替代物。适体是具有以高亲和性和特异性识别实际上任何类型靶分子能力的寡核苷酸或寡肽序列。此类配体可以通过对随机序列文库进行的指数富集的配基系统进化(SELEX)分离,如Tuerk C.和Gold L.,1990中所述。随机序列文库可通过DNA的组合化学合成来获得。在此文库中,每个成员是独特序列的最终化学修饰的线性低聚体。此类分子的可能修饰、用途和优点已经在Jayasena S.D.,1999中进行了综述。肽适体包括通过双杂交方法从组合文库中选择的通过平台蛋白,诸如大肠杆菌硫氧还蛋白A展示的构象限制的抗体可变区(Colas等,1996)。
在如上所述产生针对血清素5-HT3受体的适体后,本领域技术人员可以容易地选择阻断血清素5-HT3受体活化的那些。
根据本发明使用的血清素5-HT3受体拮抗剂可以通过本领域当前水平所述的筛选方法进一步鉴定。本发明的筛选方法可以根据已知方法进行。筛选方法可以借助于与候选化合物直接或间接结合的标记测量候选化合物与5-HT3受体的结合,或与携带5-HT3受体的细胞或膜的结合,或与其融合蛋白的结合。备选地,筛选方法可以包括测量或,定性地或定量地,检测标记的竞争物(例如,拮抗剂或激动剂)对候选化合物与5-HT3受体的结合的竞争。此外,筛选方法可以使用适于携带该受体的细胞的检测系统来测试,候选化合物是否导致由受体的拮抗剂产生的信号。拮抗剂可以在已知激动剂(例如,血清素)的存在下进行测定,并且观察候选化合物的存在对激动剂导致的活化的作用。使用已知的激动剂诸如血清素的竞争结合也是适合的。化合物针对血清素5-HT3受体的拮抗活性可以通过使用本领域众所周知的多种方法来测定。例如,5-HT3拮抗活性可以在放射性配体结合测定中和大鼠中5-HT-诱发的von Bezold-Jarisch反射中评价,例如由Turconi M.等(1990)所述。
本发明的另一个方面涉及用于治疗病灶性前庭功能障碍的血清素5-HT3受体基因表达抑制剂。
根据另一个方面,本发明涉及在用于恢复患有病灶性前庭功能障碍的受试者的前庭功能的方法中使用的血清素5-HT3受体基因表达抑制剂。
“基因表达抑制剂”是指具有抑制或显著降低基因表达的生物效应的天然或合成的化合物。因此,“血清素5-HT3受体基因表达抑制剂”是指具有抑制或显著降低编码血清素5-HT3受体的基因表达的生物效应的天然或合成的化合物。
在本发明中使用的血清素5-HT3受体基因表达抑制剂可以基于反义寡核苷酸构建体。反义寡核苷酸,包括反义RNA分子和反义DNA分子将在细胞中通过与血清素5-HT3受体mRNA结合并且由此阻止蛋白翻译或增加mRNA降解来发挥作用以直接阻断5-羟色胺5-HT3受体mRNA的翻译,由此降低血清素5-HT3受体的水平,并且因此降低其活性。例如,可以通过例如常规的磷酸二酯技术合成与编码血清素5-HT3受体的mRNA转录物序列的独特区域互补的至少约15个碱基的反义寡核苷酸,并且通过例如静脉内注射或输注施用。使用反义技术特异性地抑制其序列已知的基因的基因表达的方法在本领域中是公知的(例如,参见美国专利号6,566,135;6,566,131;6,365,354;6,410,323;6,107,091;6,046,321;和5,981,732)。
小抑制性RNA(siRNA)也可以作为在本发明中使用的血清素5-HT3受体基因表达抑制剂起作用。血清素5-HT3受体基因表达可以通过使受试者或细胞与小双链RNA(dsRNA),或导致产生小双链RNA的载体或构建体接触使得特异性地抑制血清素5-HT3受体基因表达(即,RNA干扰或RNAi)来减少。为其序列已知的基因选择适宜的dsRNA或编码dsRNA的载体的方法在本领域中是公知的(例如,参见Tuschl,T.等,(1999);Elbashir,S.M.等,(2001);Hannon,GJ.(2002);McManus,MT.等(2002);Brummelkamp,TR.等(2002);美国专利号6,573,099和6,506,559;以及国际专利申请公开号WO 01/36646,WO99/32619,和WO 01/68836)。
核酶也可以充当在本发明中使用的血清素5-HT3受体基因表达抑制剂。核酶是能够催化RNA特异性切割的酶促RNA分子。核酶的作用机制涉及核酶分子与互补靶RNA的序列特异性杂交,然后是核酸内切酶切割。因此特异性地和有效地催化血清素5-HT3受体mRNA序列的核酸内切酶切割的工程改造的发夹或锤头基序核酶分子在本发明的范围内是可用的。通过对靶分子扫描核酶切割位点初步鉴定任何潜在RNA靶标内的特异性核酶切割位点,其有代表性地包括下列的序列:GUA、GUU和GUC。一旦鉴定出,就可以评价与包含所述切割位点的靶基因的区域对应的约15至20个核糖核苷酸之间的短RNA序列的预测结构特征,例如可能使寡核苷酸序列不适合的二级结构。候选靶标的适合性也可以通过使用,例如核糖核酸酶保护测定测试它们与互补寡核苷酸杂交的可接近性来评价。
可用作血清素5-HT3受体基因表达抑制剂的反义寡核苷酸和核糖酶均可以通过已知方法制备。这些方法包括用于化学合成的技术,诸如,例如,通过固相亚磷酰胺化学合成。备选地,反义RNA分子可以通过编码RNA分子的DNA序列的体外或体内转录产生。此类DNA序列可以整合入很多种载体中,所述载体整合有合适的RNA聚合酶启动子诸如T7或SP6聚合酶启动子。可以对本发明的寡核苷酸进行多种修饰以增加细胞内稳定性和半衰期。可能的修饰包括但不限于向分子的5′和/或3′端添加核糖核苷酸或脱氧核糖核苷酸的侧翼序列,或在寡核苷酸主链内使用硫代磷酸酯或2′-O-甲基而非磷酸二酯酶键。
本发明的反义寡核苷酸siRNA和核酶可以在体内单独递送或与载体结合递送。最广义的″载体″是能够促进反义寡核苷酸siRNA或核酶核酸转移至细胞和优选地表达血清素5-HT3受体的细胞的任何运载工具。优选地,该载体以相对于在缺少所述载体时导致的降解程度而言较少的降解将核酸运送至细胞。通常,可用于本发明的载体包括,但不限于,质粒、噬菌粒、病毒、已经通过插入或结合反义寡核苷酸siRNA或核酶核酸序列而操作的来自病毒或细菌来源的其他运载工具。病毒载体是优选载体类型,并且包括,但不限于,来自下列病毒的核酸序列:逆转录病毒,诸如莫洛尼鼠白血病病毒、harvey鼠肉瘤病毒、鼠乳腺肿瘤病毒和rouse肉瘤病毒;腺病毒、腺伴随病毒;SV40-型病毒;多瘤病毒;EB病毒;乳头瘤病毒;疱疹病毒;痘苗病毒;脊髓灰质炎病毒;和RNA病毒诸如逆转录病毒。人们可以容易地采用没有提及但在本领域中已知的其他载体。
优选的病毒载体基于非细胞病变性真核病毒,其中非必需基因已经被目的基因替换。非细胞病变性病毒包括逆转录病毒(例如,慢病毒),其生命周期包括病毒基因组RNA逆转录为DNA,随后前病毒整合进宿主细胞DNA中。逆转录病毒已经被批准用于人类基因治疗临床试验。最有用的是复制缺陷的那些逆转录病毒(即,能够指导所需蛋白的合成,但不能够制造感染性颗粒)。此类遗传改变的逆转录病毒表达载体具有在体内高效转导基因的通用性。用于产生复制缺陷型逆转录病毒的标准方案(包括将外源性遗传物质整合至质粒中,用质粒转染包装细胞系,由该包装细胞系产生重组逆转录病毒,从组织培养基中收集病毒颗粒,和用病毒颗粒感染靶细胞的步骤)在Kriegler,1990和Murry,1991中提供)。
用于某些应用的优选病毒是腺病毒和腺伴随病毒,它们是已经批准用于人类基因治疗用途的双链DNA。腺伴随病毒可以被改造成复制缺陷型的,并且能够感染宽范围的细胞类型和物种。其还具有下列优点,诸如,热和脂质溶剂稳定性;在不同谱系细胞包括造血细胞中的高转导频率;以及缺乏超感染抑制,因此允许进行多重系列转导。据报道,腺伴随病毒可以以位点特异性方式整合至人细胞DNA中,从而使插入诱变的可能性和所插入的逆转录病毒感染特征性的的基因表达变异性最小化。另外,野生型腺伴随病毒感染已经在组织培养中在缺少选择压力的条件下传代超过100代,提示腺伴随病毒基因组整合是相对稳定的事件。腺伴随病毒也可以以染色体外方式起作用。
其他载体包括质粒载体。质粒载体在本领域中已被广泛地描述并且对于本领域技术人员来说是众所周知的。参见,例如,Sambrook等,1989。在过去几年中,质粒载体已经被用作DNA疫苗以在体内将编码抗原的基因递送至细胞。它们对于此是特别有利的,因为它们没有与许多病毒载体相同的安全性问题。然而,这些质粒具有与宿主细胞相容的启动子,可以从所述质粒内有效编码的基因表达肽。一些常用的质粒包括pBR322、pUC18、pUC19、pRC/CMV、SV40和pBlueScript。其他质粒是本领域普通技术人员众所周知的。另外,质粒可以使用限制性酶和连接反应进行定制设计以去除和添加特定的DNA片段。质粒可以通过多种胃肠外、粘膜和局部途径递送。例如,DNA质粒可以通过肌肉内、皮内、皮下或其他途径注射。其也可以通过鼻内喷雾剂或滴剂、直肠栓剂和口服施用。其也可以使用基因枪施用至表皮中或粘膜表面。质粒可以以水溶液提供,在金颗粒上干燥或与另一种DNA递送系统结合,所述另一种DNA递送系统包括但不限于脂质体、树状聚体、蜗形体(cochleate)和微胶囊。
本发明的另一个目的涉及用于治疗病灶性前庭功能障碍的方法,所述方法包括向需要所述方法的受试者施用血清素5-HT3受体拮抗剂或血清素5-HT3受体基因表达抑制剂。
本发明的另一个目的涉及用于恢复患有病灶性前庭功能障碍的受试者的前庭功能性的方法,所述方法包括向需要所述方法的受试者施用血清素5-HT3受体拮抗剂或血清素5-HT3受体基因表达抑制剂。
血清素5-HT3受体拮抗剂或血清素5-HT3受体基因表达抑制剂可以以如下定义的药物组合物的形式施用。
优选地,所述拮抗剂或抑制剂以治疗有效量施用。
“治疗有效量”是指足以以任何医学治疗所适宜的合理利益/风险比治疗或预防前庭缺陷的血清素5-HT3受体拮抗剂或血清素5-HT3受体基因表达抑制剂的量。
要理解的是,本发明的化合物和组合物的总日用量将由主治医师在合理的医学判断范围内来决定。对于任何特定的患者具体的治疗有效剂量水平将取决于多种因素包括被治疗的病症和所述病症的严重度;采用的具体化合物的活性;采用的具体组合物,患者的年龄、体重、一般健康状况、性别和饮食;采用的具体化合物的给药时间、给药途径和排泄速率;治疗持续时间;与采用的具体多肽联合使用或同时使用的药物;和医疗领域中众所周知的类似因素。例如,处于本领域技术范围内的是,以低于达到预期疗效所需剂量的水平化合物的剂量并且逐渐增加剂量直至达到预期疗效。然而,产品的日剂量可以在每个成人每天0.01至1,000mg的宽范围内变化。优选地,对被治疗患者进行针对症状的剂量调整,使组合物包含0.01、0.05、0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、50.0、100、250和500mg活性成分。药物有代表性地包含约0.01mg至约500mg活性成分,优选1mg至约100mg活性成分。本发明的组合物可以包含0.01mg至500mg,优选0.05mg至250mg、0.1mg至100mg、0.5mg至50mg、1mg至25mg、2.5mg至15mg、5mg至15mg、8mg至12mg范围内的血清素5-HT3受体拮抗剂。有效量的药物通常以0.0002mg/kg至约20mg/kg体重/天,尤其是约0.001mg/kg至7mg/kg体重/天的剂量水平提供。
血清素5-HT3受体拮抗剂或血清素5-HT3受体基因表达抑制剂可以与可药用赋形剂,和任选地持续释放基质,诸如生物可降解的聚合物组合,以形成治疗性组合物。
术语“药用”或“可药用”是指当根据情况施用于哺乳动物,尤其是人时不产生不良反应、变态反应或其他不利反应的分子实体和成分。可药用载体或赋形剂指无毒的固体、半固体或液体填充剂、稀释剂、任何类型的包封材料或制剂辅料。
在本发明的药物组合物中,有效成分可以单独或与另一种有效成分组合作为与常规药物载体的混合物的单位给药形式施用于动物和人类。合适的单位给药形式包括口服形式诸如片剂、凝胶胶囊、散剂、颗粒剂和口服混悬剂或溶液剂、舌下和颊部给药形式、气雾剂、植入剂、皮下、经皮、局部、腹膜内、肌肉内、静脉内、真皮下、经皮、鞘内和鼻内给药形式和直肠给药形式。
优选地,药物组合物包含对于能够被注射的制剂为可药用的赋形剂。这些赋形剂具体而言可以是等渗的、无菌的盐水溶液(磷酸一钠、磷酸二钠、氯化钠、氯化钾、氯化钙或氯化镁等或这些盐的混合物),或干燥的,尤其是冻干的组合物,其在添加无菌水或生理盐水(根据情况而定)时能够构成可注射溶液。
适合于可注射用途的药物形式包括无菌水溶液或分散液;包含芝麻油、花生油或含水丙二醇的制剂;和用于临时制备无菌可注射溶液或分散液的无菌散剂。在所有情况下,所述形式必须是无菌的并且必须是容易注射程度的流体。其在制造和储存条件下必须是稳定的,并且必须防止微生物如细菌和真菌的污染。
包含作为游离碱或可药用盐的本发明化合物的溶液可以在与表面活性剂如羟丙纤维素适当混合的水中制备。分散液也可以在甘油、液体聚乙二醇和它们的混合物中和在油中制备。在普通的储存和使用条件下,这些制剂包含防腐剂以防止微生物的生长。
本发明的血清素5-HT3受体拮抗剂或血清素5-HT3受体基因表达抑制剂可以被配制成中性或盐形式的组合物。可药用盐包括酸加成盐(与蛋白质游离氨基形成的盐)和与无机酸诸如,例如,盐酸或磷酸,或有机酸诸如乙酸、草酸、酒石酸、扁桃酸等形成的那些酸加成盐。与游离羧基形成的盐也可以衍生自无机碱诸如,例如,氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙或氢氧化铁,和有机碱诸如异丙胺、三甲胺、组氨酸、普鲁卡因等。
载体也可以是包含例如,水、乙醇、多元醇(例如,甘油、丙二醇和液体聚乙二醇等)、其适宜混合物和植物油的溶剂或分散介质。例如,通过使用包衣,诸如卵磷脂,在分散体的情况下通过维持所需的粒度并且通过使用表面活性剂来保持适宜的流动性。通过各种抗菌剂和抗真菌剂,例如,对羟基苯甲酸酯、三氯叔丁醇、苯酚、山梨酸、硫柳汞等可以阻止微生物的作用。在许多情况下,优选包含等渗剂,例如,糖类或氯化钠。可以通过在组合物中使用延缓吸收的试剂,例如单硬脂酸铝和明胶达到可注射组合物的延长吸收。
通过将所需量的活性成分根据需要与多种上面列举的其他成分一起加入至适当的溶剂中,然后过滤除菌制备无菌注射溶液。通常,通过将多种灭菌的活性成分加入至无菌赋形剂中来制备分散液,所述无菌赋形剂包含基础分散介质和所需的来自上面列举那些其他成分。在用于制备无菌注射溶液的无菌散剂的情况下,优选的制备方法是真空干燥和冷冻干燥技术,所述技术产生活性成分以及来自其先前无菌过滤溶液的任何额外需要的成分的粉末。
在配制时,溶液将以与剂量制剂相容的方式且以治疗有效的量施用。制剂容易地以多种剂型施用,诸如上述的可注射溶液的类型,但也可以采用药物释放胶囊等。
对于以水溶液的胃肠外给药,例如,如果必需,溶液应当适当地进行缓冲,并且用足量的盐水或葡萄糖首先使液体稀释剂成为等渗的。这些特殊的水溶液尤其适合用于静脉内、肌内、皮下和腹膜内给药。就此而言,依据本公开,可以采用的无菌水性介质是本领域技术人员已知的。例如,一个剂量可以溶解在1ml等渗NaCl溶液中,并且加入至1000ml皮下输注液中或在计划的输注部位处注射。根据所治疗受试者的状况,剂量必然发生一些改变。无论如何,负责给药的人都将确定对于各个受试者的合适剂量。
本发明的血清素5-HT3受体拮抗剂或血清素5-HT3受体基因表达抑制剂配制在治疗性混合物中以包含大约0.0001至1.0毫克,或大约0.001至0.1毫克,或大约0.1至1.0或甚至大约10毫克/剂量左右。也可以施用多剂量。
除了配制用于胃肠外给药,例如静脉内或肌内注射的本发明化合物以外,其他可药用的形式包括,例如,用于口服给药的片剂或其他固体;脂质体制剂;定时释放胶囊;和目前使用的任何其他形式。
在具体的实施方案中,血清素5-HT3受体拮抗剂或血清素5-HT3受体基因表达抑制剂通过鼓膜直接施用于内耳中。为了对前庭产生直接和长期的作用,这种给药模式可能是优选的。因此,在优选的实施方案中,血清素5-HT3受体拮抗剂或血清素5-HT3受体基因表达抑制剂以凝胶制剂施用从而能够在内耳中长期释放所述拮抗剂或抑制剂。
在本发明的另一个实施方案中,本发明的组合物配制成用于经鼻给药。通过经鼻给药提供几种优势:
-可以减少活性化合物的剂量,因为其被粘膜快速吸收并且生物利用度很高
-治疗作用的起效快速
-避免肝脏首过代谢
-可以避免胃肠道中的代谢
-改善了患者依从性。
血清素5-HT3受体拮抗剂的经鼻给药途径提供了通过高度通透的鼻粘膜将活性药物快速递送至血液并且避免肝脏首过效应。此给药途径的优势是其不是侵入性的且可自身给药。另一个优点是在吸入后快速起效并且与口服给药相比具有较高的生物利用度,预期产生改善的功效。此途径也非常便于治疗在急诊室接收的患者。他们通常由于眩晕而紧张,并且经鼻途径比IV易于给药,并且比口服给药更适宜,尤其是当患者遭受恶心或正在呕吐时。
另一个优势在于在于避免额外的口服(片剂/胶囊)摄入,这在正在接受对于其他疾病的多次用药且将利用经鼻途径的老年患者中是令人关注的。在患有肝衰竭的患者中,应当推荐奥丹西隆的经鼻途径,并且其优于口服或IV途径。使用鼻制剂限制了意外过量用药的风险。
因此,本发明的一个目的是如上所述的用于治疗病灶性前庭功能障碍的血清素5-HT3受体拮抗剂,其中包含血清素5-HT3受体拮抗剂的组合物为适于经鼻给药的形式。本发明的另一个目的是用于经鼻施用用于治疗病灶性前庭功能障碍的血清素5-HT3受体拮抗剂的装置。
所述给药途径能够使活性剂获得与其他给药途径相比更好的生物利用度,并且有益于治疗可能遭受呕吐的受试者。
用于将血清素5-HT3受体拮抗剂施用至鼻腔的合适形式是滴剂或喷雾剂。喷雾装置可以是单(单位)剂量或多剂量系统,例如,包括瓶子、泵和致动器。
喷雾装置的单次动作通常分配0.04~0.25ml。典型的经鼻用药方案为向一个鼻孔单次喷雾一直到向每个鼻孔两次喷雾。
包含血清素5-HT3受体拮抗剂的组合物可以进一步包含载体或基质、pH调节剂、防腐剂、稳定剂、香料和吸收促进剂。
载体或基质的实例包括,但不限于,水、羟丙基纤维素、海藻酸、壳聚糖或γ-聚谷氨酸盐。pH调节剂的实例包括,但不限于,磷酸氢二钠、柠檬酸或柠檬酸钠。防腐剂的实例包括,但不限于,氯化钠或山梨酸钾。香料的实例包括,但不限于,D-山梨糖醇、甘草、糖精或甜叶菊。吸收促进剂的实例包括,但不限于,胆汁酸。
用于经鼻给药的本发明的组合物可以包含0.01mg至500mg,优选0.05mg至250mg、0.1mg至100mg、0.5mg至50mg、1mg至25mg、2.5mg至15mg、5mg至15mg、8mg至12mg范围内的血清素5-HT3受体拮抗剂。
用于经鼻给药的根据本发明的组合物的一个实例是包含奥丹西隆基质、氯化钠、山梨酸钾和柠檬酸盐的水基组合物。
本发明进一步通过下面的附图和实施例进行说明。然而,这些实施例和附图无论如何不应当解释为限制本发明的范围。
实施例
下面的实施例描述作出和实施本发明的一些优选方式。然而,应该离解所述实施例仅用于说明目的,且不意在限制本发明的范围。此外,除非实施例中的描述以过去式给出,否则象说明书的其余部分那样,所述文字不意在提示实际上进行了所述实验或实际上获得了所述数据。
实施例1:奥丹西隆减少了急性前庭神经炎后的前庭缺陷(图1)
方法:本发明人在蒙彼利埃的大学中心医院(Centre Hospitalier Universitaire(CHU)of Montpellier)处进行了临床研究。对20名患者进行了随机临床试验。根据怀疑在入院前前庭神经炎发作少于24小时来选择患者。患者均给予甲泼尼龙和伐昔洛韦,用甲氧氯普胺(30mg/d,n=10)治疗5天或用奥丹西隆(8mg/d,n=10)治疗5天。基于早期VNG(前庭眼震电图)测试(在前庭缺陷开始后24至48小时实施)和在1月时的VNG进行功能评价。还记录住院时间和首次行走的日期。
结果:关于早期VNG,在施用奥丹西隆的患者中前庭缺陷不太显著(56.53%相比84.38%,p=0.03)。在1月时,在两组患者中前庭缺陷没有差异(43%O相比63.4%M,p=0.07)。在奥丹西隆组住院时间显著减少(2.88相比4.5天,p=0.03)。首次行走的时间也显著较短(1.25相比2.25天,p=0.001)。
此临床研究证明奥丹西隆在减少人急性前庭神经炎后的前庭缺陷方面表现出显著的作用(图1A)。使用冷热试验对前庭功能的临床研究表明了对外周前庭终器的直接保护性或恢复性作用。该药理学作用不干扰长期中枢代偿作用。其结果是显著缓解了头晕且减少了住院时间(图1B-C)。这些临床观察表明奥丹西隆及其衍生物可能在维持和恢复前庭内的神经支配中是有用的。
实施例2:血清素5-HT3拮抗剂的细胞靶标在前庭终器中表达
先前的报道和来自发明人最近的组织学试验支持了血清素5-HT3受体拮抗剂对前庭的推定直接作用,先前报道血清素受体在内耳中表达特别是在前庭终器中表达(Johnson和Heinemann,1995;Gil-Loyzaga等,1997),而发明人的试验显示5-HT3受体蛋白存在于前庭上皮中。
方法:
药理学靶标在前庭中的免疫组织学定位。
我们用戊巴比妥(0.4%)麻醉雌性成年大鼠(Wistar;200-220g,n=2)。动物用肝素PBS(0.01M)穿心灌注,然后灌注固定溶液(4%多聚甲醛,1%苦味酸,5%蔗糖)并将样品后固定。我们将前庭神经节和上皮包埋在4%琼脂糖中,并切成40μm厚切片。在封闭溶液(在PBS中的0.5%鱼明胶,0.5%Triton X-100和1%BSA)中预孵育防止非特异性结合。然后将样品与一抗:兔抗-5HT-3A受体多克隆抗体(1∶200;AB5657;Millipore,Billerica,MA)孵育。对于对照,我们省略了所研究的一抗。二抗用Alexa 594-缀合的猴抗兔血清(1∶200,MolecularProbes,Eugene,OR)显示特异性标记。使用Zeiss 5 live duo激光扫描共聚焦显微镜(RIO imaging,Montpellier,法国)观察在载玻片上封固的样品。
结果:
如图2中所示,5HT-3受体在斯卡尔帕神经节中表达(图2A)。对于5HT-3A受体,所有初级前庭神经元(箭头)均染色,大尺寸以及小尺寸的体细胞发出免疫荧光。施旺细胞和内皮细胞未被标记。在前庭感觉上皮(图2B-D)中,感觉上皮周围的移行细胞(大箭头)和在少数神经纤维(箭头)中特异性地表达5HT-3A受体。神经丝和钙结合蛋白的共染色(数据未显示)强烈表明表达完全限于不同的传出纤维。
实施例3:奥丹西隆的恢复作用的验证
本实施例旨在在前庭缺陷的动物模型中验证在人中所观察到的选自奥丹西隆、格雷西隆、托烷司琼或帕洛诺司琼的血清素5-HT3受体拮抗剂对前庭终器的恢复作用。本实施例还旨在确定参与该过程的生物学过程(保护/修复)。这通过比较单侧和双侧前庭缺陷两个模型中应用所述血清素5-HT3受体拮抗剂条件下的组织学损害和前庭缺陷时程来评估。两个不同的前庭缺陷的动物模型的组合能够确定在单侧或双侧前庭缺陷的条件下使用所述血清素5-HT3受体拮抗剂的益处。据我们所知,它们是致力于哺乳动物前庭系统的首个范例。确定参与所述血清素5-HT3拮抗剂对前庭的恢复作用中的生物学过程能够明确将在未来临床试验中使用的治疗窗。
单侧前庭缺陷(图3-5)
通过分析耳内应用谷氨酸盐激动剂期间两个兴奋性毒性病变的出现和消除以及随后在前庭终器内发生的前庭缺陷的时程来验证所述血清素5-HT3拮抗剂的恢复作用。在前庭终器中,大量应用红藻氨酸诱发感觉器官中神经元网络的兴奋性毒性损害(接触毛细胞的末梢的肿胀-Brugeaud等,2007)。使用光学和电子显微镜开展对兴奋性毒性病变扩大和缩小的组织学研究。使用前庭功能的特异性行为测试来进行前庭缺陷的行为评价。在大鼠中开发的范例中,经鼓膜应用红藻氨酸使其扩散至内耳中。在大多数情况下,兴奋性毒性病变在12h后达到顶点,并且在2-3天内消失。在红藻氨酸损伤后1小时通过腹膜内注射所述血清素5-HT3拮抗剂研究施用所述血清素5-HT3拮抗剂后的保护作用。
方法:
单侧前庭缺陷的诱发
将一种谷氨酸能激动剂,红藻氨酸(KA)经鼓膜注射至中耳中,之后其通过圆窗扩散至内耳(前庭和耳蜗),在此其作用于传入神经纤维。这效仿导致前庭损害发生的病理学兴奋性毒性损伤机制。我们使用前庭缺陷的行为测试和对诱发病变的组织学定量评价了KA注射的作用。
奥丹西隆以4mg/kg经腹膜内注射(ip)(图3A)。
KA注射后1h,测试动物的前庭行为,紧接着在治疗组中注射奥丹西隆。对照动物不注射奥丹西隆。随后,在KA注射后2h、6h、24h和48h时测试动物。在使用奥丹西隆治疗和不治疗的条件下在KA注射后2小时和24小时时进行组织学和形态计量分析。
前庭缺陷的行为评价
前庭分级评分如以前所述那样进行评价(Brugeaud等,2007;Boadas-Vaello等2005)。分别对应于正常行为至最大前庭缺陷将动物评为0-4分。等级1是指行为不正常但不能有效地确定特异性的前庭损害;等级2对应于确定的但轻微的前庭缺陷,等级3表示确定的和明显的缺陷。相继地对6个不同的试验进行评分并且加起来评定前庭缺陷:1-当观察到颈部异常的间歇性向后伸展时的头部摆动;2-转圈的刻板运动,从没有到围绕动物臀部的强制性转圈;3-后退,典型的后退行走反应前庭失调;4-尾部-悬挂反射,当前庭缺陷为最大时,通常诱发正常前肢伸展到达地面,导致身体腹侧弯曲和尾部夹紧;5-接触-抑制反射通常使动物当其背部接触地面时以仰卧位握住金属格网而返回;在缺少身体方位指示的前庭缺陷的情况下,此反射消失,动物仍然以仰卧位抓握格网;6-空中-翻正反射,对于动物来说在其从仰卧位落下时以足着地是必不可少的;前庭功能障碍损害这种正常翻转反射,最大的缺陷导致动物在其从40cm的高度坠落至泡沫垫上时以其背着地。对于每个时间点的前庭分级评分表示为t0评分的百分比。
前庭病变的组织学评价
制备感觉上皮的半薄切片。我们用戊巴比妥(0.4%)麻醉雌性成年大鼠(Wistar;200-220g;对于每种治疗n=3)。动物用肝素PBS(0.01M)穿心灌注,然后灌注固定溶液(2多聚甲醛,2.5%戊二醛,1%苦味酸,5%蔗糖)并将样品后固定。我们包埋整个前庭器官的前庭上皮,在2%OsO4中后固定,脱水,包埋在环氧树脂中,并切成1μm厚的切片。使用Nanozoomer载玻片扫描仪(RIOimaging,Montpellier,法国)观察和扫描封固在载玻片上的样品。
分析使用Nanozoomer载玻片扫描仪获取的半薄切片的扫描图像。使用Metamorph软件(Universal Imaging)完成对椭圆囊中毛细胞的定量。对于每个病变耳和对侧耳,每一个分析距离20至25μm的3张切片。因此,对于在3只不同的动物上的每种治疗对每个上皮计数400个细胞,对侧耳作为混合对照。细胞被计数为1)当观察到其周围有神经盏的梨形细胞时计为I型毛细胞;2)当观察到有高位胞核的细长细胞时计为II型毛细胞;3)当细胞周围的肿胀的突触末梢妨碍基于其形状确定细胞类型时,当在梨形细胞周围没有观察到神经盏时,当细长细胞的核处于低位时,计为未确定型毛细胞;4)形成上皮的基底部分的支持细胞。使用ANOVA搜索统计学差异,然后通过Tukey检验在治疗间进行比较。
结果:
在经鼓膜注射红藻氨酸后,大鼠显示强烈的兴奋性毒性诱发的前庭缺陷,该前庭缺陷在48小时内逐渐减弱(图3B)。当动物用奥丹西隆治疗时此减弱的前庭缺陷的时程被改变,在24小时时前庭缺陷明显减弱(*p=0.022;曼-怀二氏检验;n≥8)。随后,由于内源性代偿机制,治疗的和未治疗的动物恢复至类似的前庭缺陷水平。
如图4A中所示,在KA经鼓膜注射后2消失,其诱发感觉上皮中前庭传入神经的大的细胞外病灶(图4A)。与对侧的无病变耳(图4C)相比,观察到沿毛细胞有大的肿胀的突触末梢,而不是典型的I型神经盏和II型神经终扣末梢。当此病变后24小时观察时,使用奥丹西隆(图4B)和不使用奥丹西隆(图4D)观察到新的神经盏和神经终扣末梢。在光子显微水平上,奥丹西隆似乎能够使这些“新形成的”突触末梢成熟。
如图5中所示,形态计量分析确定经鼓膜注射KA没有诱发毛细胞或支持细胞的损失。相反,确定的周围有神经盏的I型毛细胞的数量被KA极大地和显著地减少(P<0.001),这通过未被确定的毛细胞数量的增加证实(P<0.01)。当在细胞外损伤后24小时计数时,刚确定的I型毛细胞的数量显著增加(p<0.01),但未确定的毛细胞的数量没有显著减少。此结果证明在细胞外损伤后突触末梢修复的能力。对于奥丹西隆治疗,我们还观察到在KA病变后24小时I型毛细胞数量显著增加(p<0.01)。更有趣的是,奥丹西隆治疗显著地减少未确定的毛细胞的数量(P<0.01),反映出对细胞外损伤突触末梢的保护和/或促进修复。
在用奥丹西隆治疗后红藻氨酸诱发的前庭缺陷显著减少的这种行为观察结果(兴奋性毒性损伤后24h)可以通过防止病变扩大或被治疗大鼠中恢复过程的增强来解释。在任何情况下,均假定在奥丹西隆治疗的动物中观察到的较好的前庭状态是由较好的前庭功能有效性所支持的。组织学观察结果支持了下面的观点:在被治疗的动物中毛细胞分支分布模式被较好地保留或被较好地修复。
双侧前庭缺陷(图6)
通过分析腈中毒(IP注射-Seoane等,J.Comp.Neurol.2001,439:385-399)后两个兴奋性毒性病变的出现和消除以及随后发生的前庭缺陷的时程来验证所述血清素5-HT3拮抗剂的恢复作用。在急性应用腈后3天内,经代谢后腈诱发可确认的耳毒性/兴奋性毒性损害和前庭缺陷。通过在不同的时间方案(在慢性中毒开始时;之后24和48h)后施用所述血清素5-HT3拮抗剂来评估保护作用。
方法:
IDPN(1g/kg;ip)通过破坏前庭感觉上皮诱发双侧和永久性的前庭损害。此进行性的损伤在72小时后达到其最大程度。我们使用前庭缺陷的行为测试来评估IDPN注射的作用。我们评价了在IDPN注射后损伤进展的整个时程中单次或两次注射奥丹西隆的保护作用以确定奥丹西隆的前庭保护潜力。奥丹西隆的每个剂量以4mg/kg经腹膜内(ip)注射。
我们使用了4种治疗范例(图6A):
A.同时注射奥丹西隆(1个剂量)和IDPN。
B.IDPN注射后24小时注射奥丹西隆(1个剂量)。
C.IDPN注射后48小时注射奥丹西隆(1个剂量)。
D.IDPN注射后24和48小时两次注射奥丹西隆(总计2个剂量)。
在IDPN注射后6、24、30、48、54、72和96小时时进行行为测试。
结果:
当动物同时接受奥丹西隆和IDPN时,增加的前庭缺陷的时程没有显著变化(p≤0.05曼-怀二氏检验;n≥5)(图6B)。
当动物在IDPN注射后24小时用奥丹西隆治疗时,增加的前庭缺陷的时程没有显著变化(p≤0.05曼-怀二氏检验;n≥7)(图6C)。
当动物在IDPN注射后48小时用奥丹西隆治疗时,增加的前庭缺陷的时程没有显著变化(p≤0.05曼-怀二氏检验;n≥6)(图6D)。
在用IDPN诱发前庭缺陷(t=0h)后24和48小时注射奥丹西隆(2个剂量)。行为测试显示在54h时增加的前庭缺陷的时程的显著改变(p≤0.05MannWhitney检验;n≥7)。在24和48h时用奥丹西隆治疗的动物在第二次奥丹西隆注射后54h时显示显著较少的严重前庭缺陷(图6E)。
在用奥丹西隆治疗后腈诱发的前庭缺陷(毒性损伤后24h和48h)显著减少的这种行为观察结果,可以通过早期防止病变扩大而非被治疗大鼠中恢复过程的增强来解释。实际上,腈在3天内杀死毛细胞,因此阻止了如假定在红藻氨酸盐处理的动物中发生的那样神经传入纤维的任何再连接。在任何情况下,可以假定在奥丹西隆治疗的动物中观察到的较好的前庭状态是由较好的前庭功能有效性所支持的。未来的组织学研究将能够确定在被治疗的动物中在腈损伤后24h-48h时毛细胞分支分布模式是否被较好地保留。
实施例4:用于经鼻给药的包含奥丹西隆的组合物的实例。
组合物1 | 组合物2 | 组合物3 | |
奥丹西隆基质 | 8mg/ml | 10mg/ml | 6mg/ml |
氯化钠 | 0.9% | 0.9% | 0.9% |
山梨酸钾 | 0.125% | 0.125% | 0.125% |
柠檬酸盐 | qsp pH 4.5 | qsp pH 4.5 | qsp pH 4.5 |
纯水 | Qsp | Qsp | qsp |
包含奥丹西隆基质的溶液的稳定性
发现包含约8mg/ml奥丹西隆基质的溶液在25℃下保存1月和在4℃下保存1月后是物理稳定的。
还评价了溶液的化学稳定性:
这些观察结果显示pH改变没有伴随奥丹西隆的明显化学降解。没有观察到沉淀。可以通过使用柠檬酸盐缓冲液实现pH的稳定。
参考文献
在整个本申请中,多篇参考文献描述了本发明所属领域的现有技术水平。这些参考文献的公开内容因此通过参考并入本本公开中。
Brugeaud A,Travo C,Demêmes D,Lenoir M,Llorens J,Puel JL,ChabbertC.Control of hair cell excitability by vestibular primary sensory neurons.J Neurosci.2007;27(13):3503-11.
Gil-Loyzaga P,BartoloméMV,Vicente-Torres MA.Serotonergic innervationof the organ of Corti of the cat cochlea.Neuroreport.1997;8(16):3519-22.
Johnson DS,Heinemann SF.Embryonic expression of the 5-HT3 receptorsubunit,5-HT3R-A,in the rat:an in situ hybridization study.Mol Cell Neurosci.1995;6(2):122-38.
Seoane A,Demêmes D,Llorens J.Relationship between insult intensity andmode of hair cell loss in the vestibular system of rats exposed to3,3′-iminodipropionitrile.J Comp Neurol.2001;439(4):385-99.
Turconi M,Nicola M,Quintero MG,Maiocchi L,Micheletti R,Giraldo E,Donetti A.Synthesis of a new class of2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid derivatives as highly potent5-HT3 receptor antagonists.J Med Chem.1990 Aug;33(8):2101-8.
Claims (10)
1.一种用于治疗病灶性前庭功能障碍的血清素5-HT3受体拮抗剂。
2.根据权利要求1所述的血清素5-HT3受体拮抗剂,其中所述血清素5-HT3受体拮抗剂选自有机小分子、抗体和适体。
4.根据权利要求2所述的血清素5-HT3受体拮抗剂,其中所述血清素5-HT3受体拮抗剂选自:奥丹西隆、帕洛诺司琼、托烷司琼、来立司琼、阿洛司琼、格雷西隆、多拉司琼、贝美噻通、雷莫司琼、阿扎西隆、伊他司琼、扎考必利和西兰司琼。
5.根据权利要求4所述的血清素5-HT3受体拮抗剂,其中所述血清素5-HT3受体拮抗剂是奥丹西隆。
6.一种用于治疗病灶性前庭功能障碍的血清素5-HT3受体基因表达抑制剂。
7.根据权利要求6所述的血清素5-HT3受体基因表达抑制剂,其中所述血清素5-HT3受体基因表达抑制剂选自反义RNA或DNA分子、小抑制性RNA(siRNA)和核酶。
8.根据权利要求1-5中任一项所述的血清素5-HT3受体拮抗剂或根据权利要求6或7所述的血清素5-HT3受体基因表达抑制剂,其中所述前庭缺陷选自前庭神经炎、病毒性神经炎、迷路炎、病毒性内淋巴迷路炎、药物造成的耳毒性、梅尼埃病、内淋巴积液、带有病灶性前庭缺陷的头部创伤、迷路出血、慢性或急性迷路感染、浆液性迷路炎、气压创伤,自身免疫性内耳疾病、慢性梅尼埃病、老年性前庭症和中毒性前庭损害。
9.根据权利要求1-8中任一项所述的用于治疗病灶性前庭功能障碍的血清素5-HT3受体拮抗剂,其中所述血清素5-HT3受体拮抗剂通过经鼻途径施用。
10.一种装置,用于经鼻施用根据权利要求1-8中任一项所述的用于治疗病灶性前庭功能障碍的血清素5-HT3受体拮抗剂。
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CN109310698A (zh) * | 2016-04-14 | 2019-02-05 | 森索睿翁公司 | 用于治疗耳部病症的(+)-阿扎司琼 |
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WO2015073789A1 (en) * | 2013-11-14 | 2015-05-21 | Insys Pharma, Inc. | Ondansetron sublingual spray formulation |
WO2016161309A1 (en) | 2015-04-01 | 2016-10-06 | Colorado State University Research Foundation | Optimized cancer stem cell vaccines |
HUE056138T2 (hu) * | 2015-05-18 | 2022-01-28 | Sensorion | Azasetron a halláskárosodás kezelésében való felhasználásra |
US10172833B2 (en) | 2015-08-11 | 2019-01-08 | Insys Development Company, Inc. | Sublingual ondansetron spray |
EA038516B1 (ru) * | 2016-07-19 | 2021-09-09 | Сенсорьон | Композиция для лечения заболеваний уха, содержащая (+)-азасетрон |
JP2019210240A (ja) * | 2018-06-04 | 2019-12-12 | 学校法人慶應義塾 | 衝動抑制薬のスクリーニング方法、及び衝動抑制薬 |
KR102514860B1 (ko) | 2020-12-01 | 2023-03-29 | 한국과학기술연구원 | 5-ht7 세로토닌 수용체 활성 저해용 바이페닐 피롤리딘 및 바이페닐 다이하이드로이미다졸 유도체 및 이를 유효성분으로 포함하는 약학 조성물 |
US11986464B2 (en) * | 2021-04-30 | 2024-05-21 | University Of Kentucky Research Foundation | 5HT3R antagonist for use in treating aneurysms and cardiovascular risk |
WO2023190707A1 (ja) * | 2022-03-30 | 2023-10-05 | 国立大学法人大阪大学 | 感音難聴の予防または治療用組成物 |
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---|---|---|---|---|
CN109310698A (zh) * | 2016-04-14 | 2019-02-05 | 森索睿翁公司 | 用于治疗耳部病症的(+)-阿扎司琼 |
CN109310698B (zh) * | 2016-04-14 | 2021-12-24 | 森索睿翁公司 | 用于治疗耳部病症的(+)-阿扎司琼 |
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SI2432467T1 (en) | 2018-06-29 |
RU2608458C2 (ru) | 2017-01-18 |
KR101779991B1 (ko) | 2017-09-19 |
IL216258A0 (en) | 2012-01-31 |
IL216258A (en) | 2017-01-31 |
ES2664599T3 (es) | 2018-04-20 |
CA2761762A1 (en) | 2010-11-25 |
JP2015107995A (ja) | 2015-06-11 |
JP5992550B2 (ja) | 2016-09-14 |
KR20120055495A (ko) | 2012-05-31 |
WO2010133663A1 (en) | 2010-11-25 |
PL2432467T3 (pl) | 2018-07-31 |
CN102458400B (zh) | 2014-10-08 |
CY1120661T1 (el) | 2019-12-11 |
PT2432467T (pt) | 2018-04-04 |
HRP20180531T1 (hr) | 2018-06-01 |
CA2761762C (en) | 2018-09-04 |
LT2432467T (lt) | 2018-04-10 |
JP2012527430A (ja) | 2012-11-08 |
US20120064094A1 (en) | 2012-03-15 |
JP5955767B2 (ja) | 2016-07-20 |
EP2432467A1 (en) | 2012-03-28 |
RU2011151834A (ru) | 2013-06-27 |
HUE037300T2 (hu) | 2018-08-28 |
EP2432467B1 (en) | 2018-02-21 |
DK2432467T3 (en) | 2018-04-16 |
US8580730B2 (en) | 2013-11-12 |
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