CN101384254A - 能够增强gabaa能神经传递的化合物用于治疗炎性疾病的用途 - Google Patents
能够增强gabaa能神经传递的化合物用于治疗炎性疾病的用途 Download PDFInfo
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- CN101384254A CN101384254A CNA2007800052625A CN200780005262A CN101384254A CN 101384254 A CN101384254 A CN 101384254A CN A2007800052625 A CNA2007800052625 A CN A2007800052625A CN 200780005262 A CN200780005262 A CN 200780005262A CN 101384254 A CN101384254 A CN 101384254A
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Abstract
本发明涉及加波沙朵或加波沙朵与一种或多种抗炎化合物的组合在治疗炎性疾病中的应用。本发明进一步涉及含加波沙朵和一种或多种抗炎化合物的药物组合物。本发明进一步涉及其中一种或多种炎性标志物升高的疾病的治疗,包括对需要的对象给药治疗有效量的、能够增强GABAA能神经传递的化合物。
Description
技术领域
本发明涉及加波沙朵或加波沙朵与一种或多种抗炎化合物的组合在治疗炎性疾病中的应用。本发明进一步涉及含加波沙朵和一种或多种抗炎化合物的药物组合物。本发明进一步涉及治疗其中一种或多种炎性标志物升高的疾病的方法,包括向需要治疗的对象给药治疗有效量的、能够增强GABAA能神经传递的化合物。
背景技术
主要的抑制性神经递质γ氨基丁酸(GABA)的受体被分为两类:GABAA受体,它们是配体门控的离子通道超家族的成员;和GABAB受体,它们是G-蛋白偶联受体。
GABAA受体作为不同的受体亚单位家族的五聚体组件被。这种组件,在大多数受体中包括2个α亚单位、2个β亚单位和1个γ或δ亚单位,决定了这些功能受体的药理学。苯并二氮杂类化合物的结合位点在α和γ亚单位的交界处,而GABA和其他GABAA激动剂的结合位点在α和β亚单位的交界处。
GABAA受体的组件确实存在,其中包括α1β2γ2、α1β2/3γ2、α3βγ2/3、α5β3γ2/2、α6βγ2α6β2δ、α4βδ和α4β2γ2。包含α1亚单位的亚型出现在绝大多数脑区中,并可能对很多苯并二氮杂类化合物的功能有贡献。
在很多临床疾病中,抑制性GABA系统的活动减退被推断为潜在的病理学机制。
加波沙朵(4,5,6,7-四氢异噁唑并[5,4-c]吡啶-3-醇)(THIP)在欧洲专利EP0000338和欧洲专利EP 0840601中被描述,并已在睡眠障碍的治疗中显示了很强的活性。加波沙朵具有以下结构:
加波沙朵可以通过现有技术中广为人知的方法制备。例如,欧洲专利EP0000338中公开的下述反应式展示了从已知起始物质全合成加波沙朵的过程。
(4,5,6,7-四氢异噁唑并[5,4-c]吡啶-3-醇)
炎症反应是免疫系统对感染和刺激的第一反应。炎性疾病的典型特征在于一种或多种以下症状:发红、关节肿胀触痛、关节痛、关节强直和关节功能丧失。目前有一些治疗可用于减轻关节痛、肿胀和炎症反应,如非甾体抗炎药(NSADs)、皮质激素(如,去氢可的松)、抗疟药(如,羟氯喹)和对乙酰氨基酚。
美国专利申请US 2005/0288371公开了加波沙朵在制备治疗神经性疼痛、纤维肌痛或类风湿性关节炎药物中的应用。根据公开的内容,加波沙朵被发现能够抑制福尔马林疼痛模型的第2期中的疼痛反应。
仍然存在开发具有改善的抗炎活性制剂的需要。
发明概述
本发明已经发现加波沙朵能显著地减少前炎症介质的释放,并且因此可用于治疗炎性疾病。没有受到任何特殊理论的束缚,本发明人创立了加波沙朵激活神经胶质细胞GABA受体,使它们超极化并导致前炎症介质释放的减少的理论。这接下来减轻了炎症反应。
根据本发明一个具体实施方式,当加波沙朵或其药学上可接受的盐被单独给药或与一种或多种抗炎化合物或其药学上可接受的盐组合给药时,可用于有效地治疗炎性疾病。在另一个具体实施方式中,炎性疾病不是类风湿性关节炎。
本发明的另一个具体实施方式是向需要治疗的对象单独给药有效量的加波沙朵或其药学上可接受的盐,或与一种或多种抗炎化合物或其药学上可接受的盐组合给药来治疗炎性疾病的方法。在另一具体实施方式中,加波沙朵的给药量对治疗炎性疾病有效,但小于睡眠诱导的剂量。在一个实施例中,给药对象未患有类风湿性关节炎。在另一个具体实施方式中,给药对象未患有类风湿性关节炎、纤维肌痛、神经性疼痛或上述几项的任何组合。
另一个具体实施方式是含加波沙朵或其药学上可接受的盐和一种或多种抗炎化合物或其药学上可接受的盐的药物组合物。在另一具体实施方式中,药物组合物包括抗炎有效量的加波沙朵和抗炎化合物。
本发明还涉及加波沙朵或其药学上可接受的盐单独使用,或与一种或多种抗炎化合物或其药学上可接受的盐组合使用以减轻炎症反应,增强免疫反应,增强对细菌和病毒感染的抵抗力,增强人总淋巴细胞计数(如,在患有细菌或病毒感染的病人中),治疗免疫低下病人,加速伤口愈合,治疗伤口长期不愈,加快术后康复,加快烧伤病人康复,或减少烧伤病人住院治疗的用途,包括给需要的对象单独给药治疗有效量的加波沙朵或与一种或多种抗炎化合物组合给药。
本发明还涉及治疗其中一种或多种炎性标志物升高的疾病的方法,包含向需要治疗的对象给药治疗有效量的、能够增强GABAA能神经传递的化合物。在另一实施例中,本发明涉及含有增强GABAA能神经传递的化合物和一种或多种抗炎化合物或其药学上可接受的盐的药物组合物。
本发明还涉及本发明的化合物在生产用于治疗其中一种或多种炎性标志物升高的疾病的药物组合物中的应用。在一个具体实施方式中,所述疾病是炎性疾病。在另一个实施例中,所述炎性疾病不是类风湿性关节炎。
发明详述
定义
在这里使用的词语“炎性疾病”是指可以由感染或非感染因素引起的急性或慢性的炎症状态。各种感染因素包括脑膜炎、脑炎、葡萄膜炎、结肠炎、结核病、皮炎和成人呼吸不良综合征。非感染因素包括外伤(烧伤、切割伤、挫伤、压伤)、自身免疫病和组织排异反应。因此,在特殊的具体实施方式中,炎症状态选自以下状态:动脉粥样硬化(动脉硬化);自身免疫疾病,例如多发性硬化症、系统性红斑狼疮、风湿性多肌痛(PMR)、痛风性关节炎、退行性关节炎、腱炎、粘液囊炎、牛皮癣、纤维变性、关节骨炎、类风湿性关节炎和其他形式的炎性关节炎、舍格伦综合征、进行性全身性硬化症(硬皮病)、强直性脊柱炎、多肌炎、皮肌炎、天疱疮、类天疱疮、I型糖尿病、重症肌无力、桥本氏甲状腺炎、格雷夫症、古德帕斯彻氏病、混合型结缔组织病、硬化性胆管炎、炎性肠道疾病,包括克罗恩病(节段性回肠炎)和溃疡性结肠炎、恶性贫血、炎性皮肤病;常见间质性肺尘症(UIP)、石棉沉着病、矽肺、支气管扩张、铍中毒、滑石病、所有形式的肺尘症、结节病(在肺和其他任何器官中)、脱屑性间质性肺炎、淋巴样间质性肺炎、巨细胞间质性肺炎、细胞间质性肺炎、外源性变应性肺泡炎、韦氏肉芽肿病和相关形式的脉管炎(颞动脉炎和结节性多动脉炎);非自身免疫性炎性皮肤病;慢性活动性肝炎;延迟型过敏反应(如,毒漆藤皮炎);肺炎或与任何原因有关的其他呼吸道炎症;由任何病因引起的成人呼吸窘迫综合征(ARDS);并发炎性水肿的脑炎;快速过敏反应,包括但不限于哮喘、花粉症、皮肤变应性、急性过敏反应;与免疫复合物急性沉积有关的疾病,包括但不限于风湿热、与任何病因有关的急性和/或慢性肾小球肾炎,包括特异性感染后(如,链球菌感染后)肾小球肾炎、系统性红斑狼疮急性恶化;肾盂肾炎;蜂窝组织炎;膀胱炎;急性和/或慢性胆囊炎;和胃肠道、膀胱、心脏或其他器官的任何部分发生的暂时性缺血,特别是那些倾向于破裂的情况;器官移植或同种异体移植组织后遗症,包括同种异体器官或组织移植后急性期阶段的同种异体移植物排斥和慢性宿主-移植物排斥。“炎性疾病”的词语也包括阑尾炎、动脉炎、睑炎、细支气管炎、支气管炎、宫颈炎、胆管炎、绒毛膜羊膜炎、结膜炎、泪腺炎、皮肌炎、心内膜炎、子宫内膜炎、肠炎、小肠结肠炎、上髁炎、附睾炎、筋膜炎、纤维组织炎、胃炎、胃肠炎、龈炎、回肠炎、虹膜炎、喉炎、脊髓炎、心肌炎、肾炎、脐炎、卵巢炎、睾丸炎、骨炎、耳炎、胰腺炎、腮腺炎、心包炎、咽炎、胸膜炎、静脉炎、肺炎、直肠炎、前列腺炎、鼻炎、输卵管炎、鼻窦炎、口腔炎、滑膜炎、扁桃体炎、眼葡萄膜炎、阴道炎、血管炎、外阴炎和外阴阴道炎、脉管炎、慢性支气管炎、骨髓炎、视神经炎、颞动脉炎、横贯性脊髓炎、坏死性筋膜炎、肝炎和坏死性小肠结肠炎。
任何抗炎化合物或其药学上可接受的盐都可以和加波沙朵组合用于炎性疾病的治疗,或用于根据本发明所述的炎症和疼痛的治疗。适合的抗炎化合物包括但不限于:非甾体抗炎药(NSAIDs,例如阿司匹林、布洛芬、萘普生、水杨酸甲酯、二氟苯水杨酸、吲哚美辛、舒林酸、双氯芬酸、酮洛芬、酮咯酸、卡洛芬、非诺洛芬、甲芬那酸、吡罗昔康、美洛昔康、塞来考昔、伐地考昔、帕瑞考昔、艾托考昔和尼美舒利)、皮质激素(如,去氢可的松、倍他米松、布地奈德、可的松、地塞米松、氢化可的松、甲基泼尼松龙、泼尼松龙、tramcinolone和氟替卡松)、抗疟药(如,羟氯喹)、对乙酰氨基酚、糖皮质激素、甾类物质、β-激动剂、抗胆碱能药、甲基黄嘌呤、金注射剂、柳氮磺胺吡啶、青霉胺、抗血管生成药、氨苯砜、香豆素、抗病毒药和抗生素。
在这里使用的词语“对象”是指任何哺乳动物。用加波沙朵治疗的对象,例如人,可以是人类种群的任何部分,男性或女性,可以分为儿童,成人和老人。这些患者组中的任何一个都是本发明的一个具体实施方式。在一个具体实施方式中,对象是老年人。在另一个具体实施方式中,对象没有患有睡眠障碍和睡眠疾病。
在这里使用的词语“药学有效量”指给药于对象后,足够产生有效反应(如,研究人员、兽医、医生或临床医师寻求的组织、系统、动物或人类的生物学或医学反应)的化合物或药物组合物的量/剂量。“药学有效量”会根据疾病及其严重性以及治疗对象的年龄、体重、身体情况和对治疗的反应而不同。
在这里使用的词语“治疗”是指阻止或延缓可能患有或容易患上疾病或状况的、而不是已经显示出疾病或状况的临床或亚临床症状的对象的疾病或状况的症状的出现。“治疗”也指抑制疾病或状况,如阻断或减少其发展或其至少一种临床或亚临床症状。“治疗”进一步指减轻疾病或状况,如引起疾病或状况或至少一种临床或亚临床症状的衰退。对治疗对象的益处是统计学显著的或对治疗对象和/或医生来说是感觉得到的。
在这里使用的词语“药学上可接受的”是指通常认为安全的分子实体和组合物,例如,当给药给人时,生理学上可耐受和不产生明显过敏反应或类似不想要的反应,例如胃部不适及类似症状。在另一个具体实施方式中,这个词语指被联邦或州政府的常设机构批准的或列于美国或其他通常认可的药典中的可用于动物的、尤其是人的分子实体或组合物。
在整个说明书中,“加波沙朵”倾向于包括这个化合物的任何形式,如游离碱(两性离子),药学上可接受的盐,例如药学可接受的酸加合盐,碱或盐的水和物或溶剂化物,以及脱水产物和无定型或结晶形式。
在一个进一步的具体实施方式中,加波沙朵选自两性离子,尽管脱水产物也是适合的,典型的是其水合物。一个适合的具体实施方式是两性离子单水合物。
在一个进一步的具体实施方式中,加波沙朵选自酸加合盐,典型的是药学上可接受的酸加合盐。一个适合的具体实施方式是有机酸加合盐,例如马来酸、反丁烯二酸、苯甲酸、抗坏血酸、草酸、二亚甲基水杨酸、甲磺酸、乙烷二磺酸、乙酸、丙酸、酒石酸、水杨酸、柠檬酸、葡萄糖酸、乳酸、苹果酸、扁桃酸、肉桂酸、柠康酸、天冬氨酸、硬脂酸、棕榈酸、衣康酸、乙醇酸、对氨基苯甲酸、谷氨酸、苯磺酸或茶碱乙酸加合盐,以及8-卤素茶碱,如8-溴-茶碱中的任何一个。另一个适合的具体实施方式是无机酸加合盐,例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸或硝酸加合盐中的任何一个。
在另一个具体实施方式中,加波沙朵以盐酸盐、氢溴酸盐或两性离子单水合物的形式存在。
在进一步的具体实施方式中,加波沙朵是结晶状的,如结晶盐酸盐、结晶氢溴酸盐或结晶两性离子单水合物。
本发明的酸加合盐可通过加波沙朵和酸在惰性溶剂中利用已知方法沉淀、分离和选择性的重结晶来得到,如果需要,可通过湿法或干法研磨或另一便利的方法将结晶产物微粉化,或通过溶剂乳化过程制备颗粒。例如,适合的方法在欧洲专利EP 0000338中被描述了。
盐的沉淀典型地在惰性溶剂,例如惰性极性溶剂如醇类(如,乙醇、2-丙醇和正丙醇)中进行,但是水或水和惰性溶剂的混合物也可以被使用。
在另一个具体实施方式中,增强GABAA能神经传递的化合物选自GABAA激动剂、GABAA受体复合物异构调节剂和GABAA吸收抑制剂。在一个具体实施方式中,增强GABAA能神经传递的化合物选自加波沙朵、环丙基GABA、异去甲槟榔次碱、蝇蕈醇、咪唑-4-乙酸,加巴喷丁和硫加宾及其药学上可接受的盐。在另一个具体实施方式中,炎性标志物选自ApoA1(载脂蛋白A1)、β-2微球蛋白、丛生蛋白、CRP(C反应性蛋白)、半胱氨酸蛋白酶抑制剂-C、嗜酸细胞活化趋化因子、因子VII、FGF-9(成纤维细胞生长因子-9)、GCP-2(粒细胞趋化蛋白-2)、生长激素、IgA(免疫球蛋白A)、IL-10(白介素-10)、IL-1β(白介素-1β)、IL-2(白介素-2)、IL-4(白介素-4)、IL-5(白介素-5)、胰岛素、IP-10(可诱导蛋白-10)、来普汀、LIF(非白血性白血病抑制因子)、MDC(巨噬细胞衍生的趋化因子)、MIP-1α(巨噬细胞炎性蛋白-1α)、MIP-1β(巨噬细胞炎性蛋白-1β)、MIP-1γ(巨噬细胞炎性蛋白-1γ)、MIP-2(巨噬细胞炎性蛋白-2)、MIP-3β(巨噬细胞炎性蛋白-3β)、MPO(髓过氧化酶)、肌红蛋白、中性粒细胞明胶酶相关脂笼蛋白(脂笼蛋白-2)、OSM(制瘤素M)、骨桥蛋白、SAP(血清淀粉状蛋白P)、SCF(干细胞因子)、SGOT(血清谷草转氨酶)、TIMP-1(1-型金属蛋白酶组织抑制剂)、组织因子、TPO(血小板生成素)和VEGF(血管内皮细胞生长因子)。
在另一个具体的实施方式中,其中炎性标志物升高的疾病是炎性疾病。在另一个具体实施方式中,所述炎性疾病不是类风湿性关节炎。
在另一个具体实施方式中,将增强GABAA能神经传递的化合物与一种或多种抗炎化合物或其药学上可接受的盐组合给药。在另一个具体实施方式中,药物组合物包含一个增强GABAA能神经传递的化合物和一种或多种抗炎化合物,所述增强GABAA能神经传递的化合物选自GABAA激动剂、GABAA受体复合物异构调节剂和GABAA吸收抑制剂。在一个实施例中,所述化合物选自加波沙朵、环丙基GABA、异去甲槟榔次碱、蝇蕈醇、咪唑-4-乙酸、加巴喷丁和硫加宾及其药学上可接受的盐。在另一个实施例中,药物组合物包含一个增强GABAA能神经传递的化合物和一种或多种抗炎化合物,增强GABAA能神经传递的化合物和抗炎化合物合用量对治疗炎性疾病有效。
给药方案
本发明也提供了其中上述药剂被以单位剂量给药的用途。在本发明的另一个具体实施方式中,单位剂量含10微克/千克体重到10毫克/千克体重的活性成分,在另一个具体实施方式中,含25微克/天/千克到1.0毫克/天/千克,在又一个具体实施方式中含大约含0.1毫克/天/千克体重到1.0毫克/天/千克体重。在另一个具体实施方式中,单位剂量含0.1毫克/天/千克体重到1.0毫克/天/千克体重的活性成分。
根据本发明,上面提到的化合物可以以碱的形式或其药学可接受的酸加合盐或所述盐的脱水物或水合物的形式被使用。根据本发明,上面提到的化合物或其药学可接受的盐可以以任何适当的途径被给药,如,经口的或非经口的,并且可以以适合上述给药途径的形式出现,如,呈片剂、胶囊、粉剂、糖浆或注射用溶液或分散剂的形式。在另一个具体实施方式中,与本发明的目的相一致的,本发明的化合物以固体药物实体的形式被给药,适合的形式是片剂或胶囊或注射用混悬液、溶液或分散剂。本发明的化合物是最方便口服给药的单位剂量的形式,如含10微克/千克体重到10毫克/千克体重,例如25微克/天/千克到1.0毫克/天/千克的活性成分的片剂或胶囊。
加波沙朵可以以口服剂量形式,如固体口服剂量形式,典型的是片剂或胶囊被给药,或以液体口服剂量形式给药。加波沙朵可以以快速释放剂量形式或控释、缓释剂量形式被给药。根据一个具体实施方式,加波沙朵以小于引起睡眠的剂量存在于控释或缓释剂量形式。加波沙朵可以是方便口服给药的单位剂量的形式,如含大约0.1到150毫克/天,大约0.2到100毫克/天,大约0.5到50毫克/天,大约0.1到50毫克/天,大约1到15毫克/天或大约2到5毫克/天的活性成分的片剂或胶囊。典型地,药物组合物含大约0.5到20毫克,例如大约0.5毫克,大约1毫克,大约1.5毫克,大约2毫克,大约2.5毫克,大约3毫克,大约3.5毫克,大约4毫克,大约4.5毫克,大约5毫克,大约5.5毫克,大约6毫克,大约6.5毫克,大约7毫克,大约7.5毫克,大约8毫克,大约8.5毫克,大约9毫克,大约9.5毫克,大约10毫克,大约10.5毫克,大约11毫克,大约11.5毫克,大约12毫克,大约12.5毫克,大约13毫克,大约13.5毫克,大约14毫克,大约14.5毫克,大约15毫克,大约15.5毫克,大约16毫克,大约16.5毫克,大约17毫克,大约17.5毫克,大约18毫克,大约18.5毫克,大约19毫克,大约19.5毫克或大约20毫克加波沙朵。加波沙朵的量给予游离碱(两性离子)的形式计算。
在一个具体实施方式中,加波沙朵以大约2.5毫克到大约20毫克的剂量被每天一次给药(例如,在早上或下午)。在另一个具体实施方式中,加波沙朵以延长和持续释放的形式被给药,其中加波沙朵的浓度不诱导睡眠,例如,以用现有技术已知的传统方法制成低剂量或修改的释放形式每天2-3次给药,如大约5毫克到大约50毫克加波沙朵以24小时为周期。在又一个具体实施方式中,加波沙朵被以低于睡眠诱导的剂量给药。
根据本发明,加波沙朵或其药学上可接受的盐可以以任何适当的途径被给药,如,经口的或非经口的途径,并且可以以适合上述给药途径的形式出现,如,以片剂、胶囊、粉剂、糖浆或注射用溶液或分散剂。在另一个具体实施方式中,与本发明的目的相一致的,本发明的化合物以固体药物实体的形式被给药,适合的形式是片剂或胶囊或注射用混悬液、溶液或分散剂。此外,加波沙朵可以与药学上可接受的载体,如佐剂和/或稀释剂一起被给药。
用于制备固体或液体药物组合物的方法在现有技术中广为人知。可见,例如,Remington:The Science and Practice of Pharmacy,21st ed.,Lippincott Williams &Wilkins(2005).片剂可以通过混合活性成分和常用载体,如佐剂和/或稀释剂,然后在压片机中压制所述混合物的方法来制备。非限制性的佐剂和/或稀释剂包括:玉米淀粉、乳糖、滑石、硬脂酸镁、白明胶、乳糖、树胶和类似物。任何其他能与活性成分配伍的佐剂或添加剂例如着色剂、香料和防腐剂都可使用。本发明的药物组合物因此典型的包括有效量的加波沙朵和药学可接受的载体。
一个合适的加波沙朵的组合物描述于WO 02/094225。倾向于不以任何限制的方式,这个专利申请中的任何一个方面和具体实施方式都适用于本发明描述的药剂或药物组合物。例如,名为“加波沙朵颗粒制剂”的WO 02/094225涉及一种特别适用于酸加合盐组合物的特定熔融颗粒,但是本申请不受这个组合物的任何限制。
药理学试验
下面的试验使用大鼠慢性应激模型(Jayatissa MN,Bisgaard C,Tingstorm A,Papp M,WIborg O.Hippocampal cytogenesis correlates to escitalopram-mediatedrecovery in a chronic mild stress rat model of depression.Neuropsychopharmacology.2006 Nov;31(11):2395-404)来评价加波沙朵对于生物化学变化引起的应激的潜在效果。应激模型在动物中诱导的生物化学变化导致炎性介质的增加。
在本研究的最后阶段,收集最终的血清样本来分析标志物以评价使用和不使用药物治疗的应激对大约60种血标志物浓度水平的影响。先期发表的数据表明慢性应激调节了很多血浆蛋白的表达。加波沙朵和依他普仑对该反应的不同调节作用是他们具有不同作用机制的指示器,并可以成为临床疗效的替代预报器。
实验过程
动物
血清样品在最后一次药物注射的24小时后的白天(09:00-17:00)取自尾部,不需将动物击昏。血样被置于含凝血激活因子和血清制备用凝胶的BD真空容器中,倒置5次并置于冰浴直到在4℃下以3000rpm离心10min。倒出血清,置于冰浴中,在一天实验完成后置于-80℃。动物的分组情况如下(见表1):
动物组
治疗代码 | 应激条件 | 药物治疗或行为 |
CMS-VEH | 慢性应激 | 运载体 |
CMS-ECT | 慢性应激 | 依他普仑 |
CMS-GBX-5mg/kg | 慢性应激 | 加波沙朵 |
CMS-GBX-10mg/kg | 慢性应激 | 加波沙朵 |
CMS-RES | 慢性应激 | 抗性的 |
NS-VEH | 未应激 | 运载体 |
NS-ECT | 未应激 | 依他普仑 |
NS-GBX | 未应激 | 加波沙朵 |
表1.动物组
分析
接下来分析血清样品的下列参数(见表2)
中位数 | 第1个研究 | 第2个研究 |
血参数 | 对照 应激 GBX ESC5mg/kg 5mg/kg | 对照 应激 GBX10mg/kg |
ApoAl(载脂蛋白Al) μg/mLβ-2微球蛋白 μg/mL钙结合蛋白 ng/mL丛生蛋白 μg/mLCRP(C反应性蛋白) ng/mL | 7.00 7.30 8.20 8.401235.00 1105.00 1140.00 1060.00 | 4.80 5.80 6.2045.00 59.00 38.000.40 0.12110.00 146.00 108.001130.00 1190.00 1030.00 |
半胱氨酸蛋白酶抑制剂-C ng/mL嗜酸细胞活化趋化因子 pg/mL因子VII ng/mIFGF-9(成纤维细胞生长因子-9) ng/mLGCP-2(粒细胞趋化蛋白-2) ng/mL生长激素 ng/mLGST-α(谷胱甘肽S-转移酶-α) ng/mLGST-μ ng/mLIgA(免疫球蛋白A) μg/mLIL-10(白介素-10) pg/mLIL-11(白介素-11) pg/mLIL-18(白介素-18) ng/mLIL-1α(白介素-1α) pg/mLIL-1β(白介素-1β) ng/mLIL-2(白介素-2) pg/mLIL-4(白介素-4) pg/mL | 1045.00 1440.00 1165.00851.00 1210.00 1300.000.38 0.95 0.59 0.900.14 0.23 0.19 0.211.66 5.67 7.67 1.387.10 6.83 5.91 6.54278.00 228.00 249.00 317.00129.00 105.00 128.00 166.000.07 0.14 0.078.12 13.80 11.30 15.4022.30 38.80 31.30 38.8024.65 46.70 29.60 51.70 | 717.00 956.00 696.001362.00 1656.00 1072.000.48 0.07 0.301.70 2.40 1.700.28 0.31 0.29112.00 23.00 3.100.89 0.402080.00 60.00 1190.005.70 7.60 4.30360.00 411.00 362.00164.00 98.000.53 0.85 0.430.53 0.65 0.5633.00 46.00 22.00 |
IL-5(白介素-5) pg/mLIL-7(白介素-7) ng/mL | 0.11 0.22 0.16 0.22 | 0.26 0.51 0.240.04 0.04 0.06 |
胰岛素 μIU/mLIP-10(可诱导蛋白-10) pg/mL来普汀 ng/mLLIF(白血病抑制因子) pg/mL淋巴细胞趋化因子 pg/mLMCP-1(单核细胞趋化蛋白-1) pg/mLMCP-3(单核细胞趋化蛋白-3) pg/mLMCP-5(单核细胞趋化蛋白-5) pg/mLM-CSF(巨噬细胞集落刺激因子) ng/mLMDC(巨噬细胞衍生的趋化因子) pg/mLMIP-1α(巨噬细胞炎性蛋白-1α) ng/mLMIP-1β(巨噬细胞炎性蛋白-1β) pg/mL | 10.90 12.20 8.88 11.3086.70 186.00 138.00 194.003.24 3.17 2.59 2.2636.60 70.50 53.90 67.2041.80 73.70 53.80 68.001095.00 1095.00 1185.00 1500.00566.00 657.00 655.00 885.000.76 0.73 0.77 0.87813.00 875.00 865.00 941.00116.00 209.00 173.00 244.00 | 9.40 3.10 14.5031.00 36.00 41.000.94 0.27 1.3549.00 93.00 67.0064.00 72.00 63.001065.00 1025.00 1020.00653.00 703.00 659.000.75 0.75 0.721960.00 1610.00 1400.000.13 0.26 0.12120.00 107.00 127.000.01 0.02 0.01 |
MIP-1γ(巨噬细胞炎性蛋白-1γ) ng/mLMIP-2(巨噬细胞炎性蛋白-2) pg/mLMIP-3β(巨噬细胞炎性蛋白-3β) ng/mLMPO(髓过氧化酶) ng/mL肌红蛋白 ng/mL中性粒细胞明胶酶相关脂笼蛋白(脂笼蛋白 ng/mL-2)OSM(制瘤素M) ng/mL骨桥蛋白ng/mLRANTES(正常T细胞表达和分泌增强调节 pg/mL因子)SAP(血清淀粉状蛋白P) μg/mISCF(干细胞因子) pg/mLSGOT(血清谷草转氨酶) μg/mI | 6.42 13.10 7.95 11.500.05 0.11 0.08 0.0989.40 53.80 20.80 54.600.21 0.12 0.17 0.22188.00 391.00 396.00 310.00135.00 173.00 133.00 178.0012.55 15.30 14.85 16.950.16 0.27 0.21 0.31 | 16.00 15.00 19.000.21 0.34 0.2221.75 13.70 29.70610.00 39.85 533.00408.00 351.00 520.000.10 0.11 0.1521.95 33.90 19.10356.00 509.00 255.0012.85 11.25 10.60241.00 198.00 403.0039.20 50.80 11.306.16 6.14 8.53 |
TIMP-1(1-型金属蛋白酶组织抑制剂) ng/mL组织因子 ng/mLTNF-α(肿瘤坏死因子-α) ng/mL | 0.09 0.28 0.16 0.220.08 0.13 0.10 0.15 | 0.37 0.77 0.240.06 0.03 0.062.55 4.14 4.45 |
TPO(血小板生成素) ng/mLVCAM-1(血管细胞粘附分子-1) ng/mLVEGF(血管内皮细胞生长因子) pg/mLvWF(vonWillebrand因子) ng/mL | 134.00 142.00 147.00 142.00299.00 381.00 361.00 409.0055.00 89.00 81.00 106.00 | 130.00 167.00 119.00330.00 311.00 353.0069.00 243.00 78.00 |
表2.各治疗组每个检验的因子的中值
数据
针对每只动物记录各个因子的浓度的数值。
结果与讨论
上面描述的药理学试验表明,与未应激的对照组相比,慢性应激能显著改变很多血清蛋白标志物。与未应激的对照组相比,CMS治疗(CMS-RES组)的大鼠没有表现出行为学反应,没有出现血清蛋白标志物的明显上调。本发明的发明人发现,与未应激的对照组相比,加波沙朵治疗能显著逆转应激诱导的血清标志物水平的改变。
因此,从前述的试验和结果,发明人发现慢性应激能显著改变一系列血清标志物蛋白的表达,加波沙朵(但不是依他普仑)对该效果的部分或全部逆转作用表明,加波沙朵通过减少炎性介质而影响应激相关的生物化学变化。因此,加波沙朵能够以剂量依赖的方式逆转或部分逆转由慢性应激引起的大部分炎症参数的变化。相反,依他普仑对大部分的变化无效。因此,加波沙朵可以用于炎症和炎性疾病的有效治疗。
所有本说明书中引用和讨论的非专利参考文献、专利和专利申请文件的完整内容在这里共同作为参考,同时每篇以同样的程度单独引入作为参考。
Claims (28)
1.一种治疗其中一种或多种炎性标志物升高的疾病的方法,包括对需要治疗的对象给药治疗有效量的、能够增强GABAA能神经传递的化合物。
2.权利要求1所述的方法,其中所述化合物选自GABAA激动剂、GABAA受体复合物的异构调节剂和GABAA吸收抑制剂。
3.权利要求1或2所述的方法,其中所述化合物选自加波沙朵、环丙基GABA、异去甲槟榔次碱、蝇蕈醇、咪唑-4-乙酸、加巴喷丁和硫加宾或其药学上可接受的盐。
4.权利要求1-3中任意一项所述的方法,其中所述炎性标志物选自Apo A1(载脂蛋白A1)、β-2微球蛋白、丛生蛋白、CRP(C反应性蛋白)、半胱氨酸蛋白酶抑制剂-C、嗜酸细胞活化趋化因子、因子VII、FGF-9(成纤维细胞生长因子-9)、GCP-2(粒细胞趋化蛋白-2)、生长激素、IgA(免疫球蛋白A)、IL-10(白介素-10)、IL-1β(白介素-1β)、IL-2(白介素-2)、IL-4(白介素-4)、IL-5(白介素-5)、胰岛素、IP-10(可诱导蛋白-10)、来普汀、LIF(非白血性白血病抑制因子)、MDC(巨噬细胞衍生的趋化因子)、MIP-1α(巨噬细胞炎性蛋白-1α)、MIP-1β(巨噬细胞炎性蛋白-1β)、MIP-1γ(巨噬细胞炎性蛋白-1γ)、MIP-2(巨噬细胞炎性蛋白-2)、MIP-3β(巨噬细胞炎性蛋白-3β)、MPO(髓过氧化酶)、肌红蛋白、中性粒细胞明胶酶相关脂笼蛋白(脂笼蛋白-2)、OSM(制瘤素M)、骨桥蛋白、SAP(血清淀粉状蛋白P)、SCF(干细胞因子)、SGOT(血清谷草转氨酶)、TIMP-1(1-型金属蛋白酶组织抑制剂)、组织因子、TPO(血小板生成素)和VEGF(血管内皮细胞生长因子)。
5.权利要求1-4中任意一项所述的方法,其中所述疾病是炎性疾病。
6.权利要求5所述的方法,其中所述炎性疾病不是类风湿性关节炎。
7.权利要求5所述的方法、其中所述炎性疾病选自脉管炎、慢性支气管炎、胰腺炎、骨髓炎、肾小球肾炎、视神经炎、颞动脉炎、脑炎、脑膜炎、横贯性脊髓炎、皮肌炎、多发性肌炎、坏死性筋膜炎、肝炎和坏死性小肠结肠炎。
8.权利要求1所述的方法,其中所述化合物与一种或多种抗炎化合物或其药学上可接受的盐被一起给药。
9.权利要求8所述的方法,其中所述抗炎化合物选自非甾体抗炎药、皮质激素、对乙酰氨基酚、糖皮质激素、类固醇、β-激动剂、抗胆碱能药、甲基黄嘌呤、金注射剂、柳氮磺胺吡啶、青霉胺、抗血管生成药、氨苯砜、香豆素、抗病毒药和抗生素。
10.权利要求1所述的方法,其中对象是人。
11.含有能够增强GABAA能神经传递的化合物和一种或多种抗炎化合物或其药学上可接受的盐的药物组合物。
12.权利要求11所述的药物组合物,其中所述抗炎化合物选自非甾体抗炎药、皮质激素、对乙酰氨基酚、糖皮质激素、类固醇、β-激动剂、抗胆碱能药、甲基黄嘌呤、金注射剂、柳氮磺胺吡啶、青霉胺、抗血管生成药、氨苯砜、香豆素、抗病毒药和抗生素。
13.权利要求11所述的药物组合物,其中所述化合物选自加波沙朵、环丙基GABA、异去甲槟榔次碱、蝇蕈醇、咪唑-4-乙酸、加巴喷丁和硫加宾或其药学上可接受的盐。
14.权利要求11所述的药物组合物,其中增强GABAA能神经传递的化合物和抗炎化合物的组合量对治疗炎性疾病有效。
15.一种治疗炎性疾病的方法,包括对需要的对象给药治疗有效量的加波沙朵或其药学上可接受的盐,条件是所述炎性疾病不是类风湿性关节炎。
16.权利要求15所述的方法,其中所述炎性疾病选自脉管炎、慢性支气管炎、胰腺炎、骨髓炎、肾小球肾炎、视神经炎、颞动脉炎、脑炎、脑膜炎、横贯性脊髓炎、皮肌炎、多发性肌炎、坏死性筋膜炎、肝炎和坏死性小肠结肠炎。
17.权利要求15所述的方法,其中将加波沙朵与一种或多种抗炎化合物或其药学上可接受的盐组合使用。
18.权利要求17所述的方法,其中所述抗炎化合物选自非甾体抗炎药、皮质激素、对乙酰氨基酚、糖皮质激素、类固醇、β-激动剂、抗胆碱能药、甲基黄嘌呤、金注射剂、柳氮磺胺吡啶、青霉胺、抗血管生成药、氨苯砜、香豆素、抗病毒药和抗生素。
19.权利要求15所述的方法,其中将加波沙朵与药学上可接受的载体一起给药。
20.权利要求15所述的方法,其中治疗有效量是从大约0.1毫克/天到大约50毫克/天。
21.权利要求20所述的方法,其中所述量小于诱导睡眠的剂量。
22.权利要求15所述的方法,其中在早晨给药加波沙朵。
23.权利要求15所述的方法,其中所述对象是人类。
24.权利要求15所述的方法,其中所述对象未患有睡眠障碍或睡眠疾病。
25.含有加波沙朵或其药学上可接受的盐以及一种或多种抗炎化合物或其药学上可接受的盐的药物组合物。
26.权利要求25所述的药物组合物,其中抗炎化合物选自非甾体抗炎药、皮质激素、对乙酰氨基酚、糖皮质激素、类固醇、β-激动剂、抗胆碱能药、甲基黄嘌呤、金注射剂、柳氮磺胺吡啶、青霉胺、抗血管生成药、氨苯砜、香豆素、抗病毒药和抗生素。
27.权利要求25所述的药物组合物,其中加波沙朵和抗炎化合物的组合量对治疗炎性疾病有效。
28.权利要求25所述的药物组合物,其中加波沙朵和抗炎化合物的组合量小于诱导睡眠的剂量。
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CN107050456A (zh) * | 2010-09-28 | 2017-08-18 | 加利福尼亚大学董事会 | 治疗代谢综合征相关疾病的gaba激动剂和治疗或预防i型糖尿病的gaba组合 |
CN107810195A (zh) * | 2014-12-04 | 2018-03-16 | 德克萨斯大学系统董事会 | 重组丛生蛋白及其在疾病治疗和预防中的应用 |
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CN107810195A (zh) * | 2014-12-04 | 2018-03-16 | 德克萨斯大学系统董事会 | 重组丛生蛋白及其在疾病治疗和预防中的应用 |
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WO2007093183A2 (en) | 2007-08-23 |
US20070203216A1 (en) | 2007-08-30 |
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EP1986627A2 (en) | 2008-11-05 |
IL193269A0 (en) | 2009-08-03 |
BRPI0707766A2 (pt) | 2011-05-10 |
TW200836723A (en) | 2008-09-16 |
CA2645734A1 (en) | 2007-08-23 |
AR059575A1 (es) | 2008-04-16 |
JP2009526786A (ja) | 2009-07-23 |
AU2007214860A1 (en) | 2007-08-23 |
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MX2008010197A (es) | 2008-09-26 |
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