CN114007690B - 治疗哮喘的方法 - Google Patents
治疗哮喘的方法 Download PDFInfo
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- CN114007690B CN114007690B CN202080044814.9A CN202080044814A CN114007690B CN 114007690 B CN114007690 B CN 114007690B CN 202080044814 A CN202080044814 A CN 202080044814A CN 114007690 B CN114007690 B CN 114007690B
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Abstract
本技术涉及治疗哮喘的方法。该方法包括向有需要的受试者施用有效量的3‑甲磺酰基丙腈(达泮舒腈(dapansutrile))或其药学上可接受的溶剂化物。优选的施用途径是口服施用或局部施用。
Description
技术领域
本技术涉及使用3-甲磺酰基丙腈(达泮舒腈(dapansutrile))或其药学上可接受的溶剂化物治疗哮喘。
背景技术
哮喘是一种常见的慢性气道病症,其特征为症状多变且反复发作,可逆性气道阻塞,支气管高反应性,和潜在的炎症。哮喘的急性症状包括咳嗽,喘息,呼吸短促,和夜间觉醒。哮喘被认为是一种慢性疾病,其基于慢性气道炎症伴有气道高反应性,至少有部分可逆性气道阻塞。
哮喘的病理生理学的核心是存在由多种细胞类型(包括肥大细胞,嗜酸性粒细胞,T淋巴细胞,巨噬细胞,树突细胞,和中性粒细胞)的募集和激活介导的潜在的气道炎症。2型辅助性T(Th2)细胞似乎在激活导致炎症的免疫级联反应中发挥核心作用。Th2衍生的细胞因子包括嗜酸性粒细胞分化和存活所需的IL-5,以及对Th2细胞分化重要的IL-4,和对IgE形成重要并导致IgE的过度产生和嗜酸性粒细胞增多的IL-13。IgE驱动的粘膜肥大细胞的激活释放支气管收缩的介质,如组胺和半胱氨酰白三烯以及炎性细胞因子。嗜酸性粒细胞含有炎性酶,产生白三烯,并表达多种促炎性细胞因子。气道上皮细胞也经由释放细胞因子(如引导和改变炎性反应的嗜酸性粒细胞趋化因子)在炎性过程中发挥作用。急性和慢性炎症不仅会影响气道管径和气流,还会增加已有的支气管对多种刺激的高反应性,从而增加对支气管痉挛的易感性。
作为气道炎症和生长因子产生的结果,气道平滑肌细胞会经历增殖,激活,收缩,和肥大;这些事件会影响气道气流限制。在哮喘中,导致临床症状的主要生理事件是气道变窄和随后的气流干扰。在哮喘急性加重时,支气管平滑肌收缩(支气管收缩)响应于暴露在多种刺激(包括过敏原或刺激物)下迅速发生以使气道变窄。过敏原诱发的急性支气管收缩是由肥大细胞释放IgE依赖性介质引起的,包括直接收缩气道平滑肌的组胺,类胰蛋白酶,白三烯,和***素。影响气道高反应性的机制是多方面的,包括炎症,神经调节功能障碍,和气道重塑。气道重塑涉及结构变化,如下基底膜(sub-basement membrane)增厚,上皮下纤维化,气道平滑肌肥大和增生,血管增殖和扩张,随之发生的气道永久性变化增加了气流阻塞。
气道上皮和内皮细胞功能也与哮喘密切相关。随着疾病的进展,上皮下基底膜增厚,粘液高分泌并形成粘液栓。内皮细胞完整性的变化导致水肿,这是定义气道哮喘变化的另一个关键病理生理学。这些因素进一步限制气流。
哮喘的特征为显性2型辅助性T细胞(Th2)免疫反应,包括增强的IL-4,IL-5,和IL-13反应,过敏原特异性免疫球蛋白产生,嗜酸性粒细胞增多,气道炎症,支气管收缩,和气道高反应性。目前哮喘的标准疗法是皮质类固醇和β2-激动剂(抗炎药物和支气管扩张药物)的联合。这些药物为许多哮喘患者提供了可接受的疾病控制。然而,据估计,尽管使用皮质类固醇和β2-激动剂的这种联合治疗,仍有5%到10%的哮喘患者有症状性疾病。
需要开发一种有效治疗哮喘的新方法。该方法应该有效且副作用最小。
附图简要说明
图1示出了第29天,即最终卵清蛋白(OVA)气溶胶激发和腹膜内注射达泮舒腈剂量的24小时后支气管肺泡灌洗液中白细胞亚群(巨噬细胞,淋巴细胞,中性粒细胞,和嗜酸性粒细胞,从左到右)的总数(平均值±SEM)。哮喘小鼠和经治疗小鼠之间的嗜酸性粒细胞****p<0.0001(每组n=8)。小鼠用60mg/kg达泮舒腈腹膜内治疗。
图2示出了用达泮舒腈治疗的小鼠肺组织中单位基底膜炎性细胞浸润的体积。哮喘小鼠和经治疗小鼠之间**p<0.01(每组n=8)。小鼠用60mg/kg达泮舒腈腹膜内治疗。
图3示出了健康小鼠,哮喘小鼠,和经治疗小鼠的杯状细胞覆盖的上皮基底膜面积(平均值±SEM)(每组n=8)。哮喘小鼠和经治疗小鼠之间**p<0.01。小鼠用60mg/kg达泮舒腈腹膜内治疗。
图4示出了健康小鼠,哮喘小鼠,和经达泮舒腈治疗的小鼠对甲基胆碱的平均值±SEM气道阻力。哮喘小鼠和经治疗小鼠之间****p<0.0001。用PBS开始MCh(乙酰-β-甲基氯化胆碱)激发试验,然后用浓度从0增加至100mg/mL的MCh气溶胶(每组n=8)。小鼠用60mg/kg达泮舒腈腹膜内治疗。
图5示出了第29天,即最终卵清蛋白(OVA)气溶胶激发和口服达泮舒腈剂量的24小时后支气管肺泡灌洗液中白细胞亚群(巨噬细胞,淋巴细胞,中性粒细胞,和嗜酸性粒细胞,从左到右,平均值±SEM)的总数。哮喘小鼠和经治疗小鼠之间的嗜酸性粒细胞****p<0.0001(每组n=8)。
图6示出了用达泮舒腈经口服治疗的小鼠肺组织中单位基底膜炎性细胞浸润的体积。哮喘小鼠和经治疗小鼠之间*p<0.05(每组n=8)。
图7示出了健康小鼠,哮喘小鼠,和经达泮舒腈治疗的小鼠对甲基胆碱的平均值±SEM气道阻力。哮喘小鼠和经治疗小鼠之间**p<0.01。用PBS开始MCh(乙酰-β-甲基氯化胆碱)激发试验,然后用浓度从0增加至100mg/mL的MCh气溶胶(每组n=8)。在饲料中以7.5g/kg食物经口服达泮舒腈治疗小鼠。
发明详述
发明人已经发现在局部和全身炎症的几种完整动物模型中降低IL-1β和IL-6水平的3-甲磺酰基丙腈有效治疗哮喘,减轻气道炎症,降低气道阻力,改善肺功能,改善哮喘症状,提高患者的生活质量。
本技术涉及治疗哮喘的方法。该方法包括向有需要的受试者施用有效量的3-甲磺酰基丙腈(达泮舒腈)化合物或其药学上可接受的溶剂化物以治疗哮喘的步骤。
如本文所用,“溶剂化物”是其中化合物与可接受的溶剂以某种固定比例结合的加成配合物。可接受的溶剂包括但不限于水,乙酸,乙醇,和其他合适的有机溶剂。
在一个实施例中,本方法在预防性治疗中有效,预防性治疗是通过在哮喘发作之前的达泮舒腈的治疗以影响发病机制来防止哮喘发展的过程。通过预防性治疗,在哮喘发作之前,向有需要的患者施用达泮舒腈。
在另一个实施例中,当患者开始表现出临床体征和/或症状时,本方法在哮喘发作之后的治疗性治疗中有效。
与哮喘相关联的肺的主要功能性变化包括免疫***功能失调,主要由嗜酸性粒细胞和中性粒细胞组成的细胞浸润,急性和慢性炎症,积液(水肿),粘液分泌过多,以及气道壁的变化,这些变化可能导致支气管上皮损伤,纤维化,和对引起支气管收缩的药剂的敏感性增加。为了开发潜在疾病过程的治疗,需要考虑这些特征。可以设计小动物模型来模拟气道炎症,对支气管收缩剂的增加的反应性,气道壁的变化,以及嗜酸性粒细胞和中性粒细胞向肺迁移的变化。例如,经由卵清蛋白致敏的哮喘小鼠模型(Lunding,2015b)可用于评估达泮舒腈的支气管扩张剂疗效。
用于治疗哮喘的本方法基于达泮舒腈的特性,以减少导致伴随该病症的病理生理学的以下过程中的至少一个:炎症,过度细胞增殖,气道和/或肺组织水肿,气道高反应性,和支气管收缩。
本方法治疗哮喘的疗效标志包括可测量的体征,症状,和其他与哮喘临床相关的变量的明显改善。这些改善包括血氧饱和度增加,缺氧和高碳酸血症减少,对补充氧气的需求减少,咳嗽和/或喘息频率降低,一秒用力呼气量(FEV1)改善,用力肺活量(FVC)或呼吸功能的其他生理相关参数改善,对机械通气的需求减少,浸润肺的炎性细胞数量减少,促炎性细胞因子和趋化因子水平降低,肺泡液清除率提高,通过任何放射照相或其他检测方法(如上皮衬液量,肺湿重与干重比,肺泡液清除,和/或放射照相可视化方法)确定的肺水肿减少,总体生活质量的提高,患者报告或医生观察到的体征,如呼吸顺畅,或咳嗽和/或喘息严重程度降低。
本方法通过(i)改善症状(白天和夜间症状,活动限制,救援药物使用),(ii)改善肺功能,如呼气流量峰值(PEF)和/或一秒用力呼气量(FEV1),和/或(iii)减少加重(比率和严重程度)来治疗哮喘。本方法提高了哮喘生活质量调查问卷(AQLQ)分数,包括症状,活动限制,情绪功能,和环境暴露的分数。
本技术已经证明,在卵清蛋白诱发的小鼠过敏性气道炎症中,达泮舒腈降低气道阻力,减少支气管肺泡灌洗液中的炎性细胞(嗜酸性粒细胞和中性粒细胞)和粘液的过度产生,并减轻气道炎症。
药学组合物
本技术提供包含一种或多种药学上可接受的载体和3-甲磺酰基丙腈的活性化合物或其药学上可接受的溶剂化物的药学组合物。药学组合物中的活性化合物或其药学上可接受的溶剂化物通常对于片剂制剂为约1-90%,对于胶囊制剂为约1-100%,对于外用制剂为约0.01-20%,或0.05-20%,或0.1-20%,或0.2-15%,或0.5-10%,或1-5%(w/w);对于注射制剂为约0.1-5%,对于贴剂制剂为0.1-5%。药学组合物中使用的活性化合物通常为至少90%,优选95%,或98%,或99%(w/w)纯。
在一个实施例中,药学组合物为剂型,如片剂,胶囊剂,颗粒剂,细颗粒剂,粉剂,糖浆剂,栓剂,可注射溶液剂,贴剂等。
在一个实施例中,药学组合物为受试者吸入的包含活性化合物的可吸入颗粒的气溶胶悬浮液的形式。可吸入颗粒可以是液体或固体,其颗粒尺寸足够小以在吸入时通过口腔和喉。一般而言,具有约1至10微米,优选1-5微米的尺寸的颗粒被认为是可吸入的。使用已知的超临界流体技术可将包括达泮舒腈的可吸入颗粒制备成干粉。在这种情况下,将化合物与适合的赋形剂混合并使用合适的溶剂或佐剂研磨成均匀物质。随后,使用超临界流体技术对该物质进行混合并获得合适的颗粒尺寸分布。制剂中的颗粒需要在想要的颗粒尺寸范围内,使得可以使用合适的吸入技术将颗粒直接吸入肺或经由机械呼吸机引入肺。
非活性成分的药学上可接受的载体可由本领域技术人员使用常规标准选择。药学上可接受的载体包括但不限于非水基溶液,悬浮液,乳液,微乳液,胶束溶液,凝胶,和软膏。药学上可接受的载体还可能包含成分,该成分包括但不限于盐水和电解质水溶液;离子和非离子渗透剂,如氯化钠,氯化钾,甘油,和葡萄糖;pH调节剂和缓冲剂,如氢氧化物盐,磷酸酯/盐,柠檬酸酯/盐,乙酸酯/盐,硼酸酯/盐;和三乙醇胺;抗氧化剂,如亚硫酸氢盐,亚硫酸盐,偏亚硫酸盐,硫代亚硫酸盐,抗坏血酸,乙酰半胱氨酸,半胱氨酸,谷胱甘肽,丁基羟基苯甲醚,丁基羟基甲苯,生育酚,和抗坏血酸棕榈酸酯的盐,酸,和/或碱;表面活性剂,如卵磷脂,磷脂,包括但不限于磷脂酰胆碱,磷脂酰乙醇胺,和磷脂酰肌醇;泊洛沙姆和泊洛沙胺(poloxamines),聚山梨酯类,如聚山梨酯80,聚山梨酯60,和聚山梨酯20,聚醚,如聚乙二醇和聚丙二醇;乙烯类聚合物,如聚乙烯醇和聚维酮;纤维素衍生物,如甲基纤维素,羟丙基纤维素,羟乙基纤维素,羧甲基纤维素,羟丙基甲基纤维素及其盐;石油衍生物,如矿物油和白凡士林;脂肪,如羊毛脂,花生油,棕榈油,大豆油;甘油单酯,甘油二酯,和甘油三酯;丙烯酸聚合物,如羧基聚亚甲基凝胶,和疏水改性的交联丙烯酸酯共聚物;多糖,如葡聚糖,和糖胺聚糖,如透明质酸钠。此类药学上可接受的载体可以使用已知的保存剂来保存以防止细菌污染,这些保存剂包括但不限于苯扎氯铵,乙二胺四乙酸及其盐,苄索氯铵,氯己定,氯丁醇,对羟基苯甲酸甲酯,硫柳汞,和苯乙醇,或可配制成用于单次或多次使用的非保存制剂。
例如,活性化合物的片剂制剂或胶囊制剂可能包含没有生物活性且不与该活性化合物反应的其他赋形剂。片剂的赋形剂可包括填充剂,粘合剂,润滑剂,和助流剂,崩解剂(disintegrators),润湿剂,和释放速率调节剂。粘合剂促进制剂颗粒的粘附,对片剂制剂很重要。粘合剂的示例包括但不限于羧甲基纤维素,纤维素,乙基纤维素,羟丙基甲基纤维素,甲基纤维素,刺梧桐胶,淀粉,淀粉,和黄着胶,聚(丙烯酸),和聚乙烯吡咯烷酮。
例如,活性化合物的贴剂制剂可能包含一些非活性成分,如1,3-丁二醇,二羟基氨基乙酸铝,依地酸二钠,D-山梨醇,明胶,高岭土,对羟基苯甲酸甲酯,聚山梨酯80,聚维酮(聚乙烯吡咯烷酮),丙二醇,对羟基苯甲酸丙酯,羧甲基纤维素钠,聚丙烯酸钠,酒石酸,二氧化钛,和纯净水。贴剂制剂还可包含皮肤渗透性增强剂,如乳酸酯(例如,乳酸月桂酯)或二甘醇单***。
包括活性化合物的外用制剂可以是凝胶,乳膏,洗剂,液体,乳液,软膏,喷雾,溶液,和悬浮液的形式。外用制剂中的非活性成分例如包括但不限于乳酸月桂酯(润肤剂/促渗剂),二甘醇单***(润肤剂/促渗剂),DMSO(溶解性增强剂),有机硅弹性体(流变学/纹理改性剂),辛酸/癸酸甘油三酯,(润肤剂),水杨酸辛酯,(润肤剂/UV过滤剂),有机硅流体(润肤剂/稀释剂),角鲨烯(润肤剂),葵花油(润肤剂),和二氧化硅(增稠剂)。
施用方法
本技术涉及治疗哮喘的方法。该方法包括以下步骤:首先识别患有哮喘或具有发展哮喘倾向的受试者,并以有效治疗哮喘的量向该受试者施用活性化合物达泮舒腈。如本文所用,“有效量”是通过改善病理状况,减轻气道炎症,降低气道高反应性,改善肺功能,和/或减轻哮喘症状来有效治疗哮喘的量。
将化合物递送至肺组织的任何方法,包括局部施用和全身施用,均适用于本技术。
全身施用包括口服,肠胃外(如静脉内,肌肉内,皮下,或直肠),和其他全身施用途径。在全身施用中,活性化合物首先到达血浆,然后分布至靶组织。
在一个实施例中,活性化合物通过局部施用递送至肺。局部施用包括吸入和靶向给药。吸入方法包括液体滴注,经由定量吸入器或等效物作为加压流体制剂滴注,经由雾化器吸入雾化溶液,吸入干粉,以及在机械通气期间将可溶或干燥物质导入气流。
在一个实施例中,通过吸入包含活性化合物的可吸入颗粒的气溶胶悬浮液将药学组合物施用于受试者。可吸入颗粒可以是液体或固体(例如,干粉),其颗粒尺寸足够小以在吸入时通过口腔和喉;一般而言,尺寸范围为约1至10微米,但更优选为1-5微米的颗粒被认为是可吸入的。经由吸入递送的活性化合物的表面浓度可根据化合物而变化;但通常为1x10-10-1x10-4摩尔/升,优选为1x10-8-1x10-5摩尔/升。
在一个实施例中,药学组合物经口服施用于受试者。口服施用剂量通常为至少0.1mg/kg/天且小于100mg/kg/天或200mg/kg/天。例如,对于人受试者,口服施用剂量为1-100,或5-50,或10-50mg/kg/天。例如,对于人受试者,口服施用剂量为100-10,000mg/天,优选500-2000,500-4000,500-4000,1000-5000,2000-5000,2000-6000,或2000-8000mg/天。该药物可以每天口服一次,两次,三次,或四次。
在一个实施例中,将药学组合物静脉内施用于受试者。静脉推注或静脉输注的剂量通常为0.03至20mg/kg/天,优选0.03至10mg/kg/天。
在一个实施例中,将药学组合物经皮下施用于受试者。皮下施用的剂量通常为0.3-20mg/kg/天,优选0.3-3mg/kg/天。
本领域技术人员将认识到,多种递送机制也适用于本技术。
本技术用于治疗哺乳动物受试者,如人,马,和狗。本技术特别适用于治疗人。
以下示例进一步说明本技术。这些示例仅旨在说明本技术而不应被解释为限制性的。
示例
示例1达泮舒腈治疗(腹膜内)减少了小鼠的过敏性气道炎症和粘液产生
使用成熟的实验过敏性哮喘小鼠模型(Sel 2008,Wegmann2005,Wegmann2007,Lunding2015a)评估达泮舒腈作为过敏性支气管哮喘的治疗选项,并确定达泮舒腈是否会影响气道炎症和气道高反应性(AHR)的发展。该模型中的炎症以嗜酸性粒细胞和TH2细胞的浸润为特征,并涉及随后的AHR和粘液过度产生的发展,从而该模型类似于人支气管哮喘的主要病理生理特征。
方法和材料
在第1天,第14天,和第21天通过3次腹膜内(i.p.)注射吸附于150mg氢氧化铝的10μg OVA使C57BL/6j小鼠被OVA(卵清蛋白)致敏。这种致敏导致OVA特异性TH2细胞对OVA的过继免疫反应并产生IgE和IgG4亚类的OVA特异性抗体。
为了诱发急性过敏性气道炎症,在第26天,第27天,和第28天将小鼠暴露于OVA气溶胶(1%w/v PBS)3次。
健康对照动物(健康组)被PBS假致敏,随后用PBS气溶胶激发。非药物治疗的动物(哮喘组)和药物治疗的动物(经治疗组)被OVA气溶胶致敏,随后用OVA气溶胶激发。治疗组在第25天,第26天,第27天,和第28天通过腹膜内(i.p.)注射60mg/kg达泮舒腈进行治疗,而健康组和哮喘组在第25天,第26天,第27天,和第28天通过腹膜内注射施用生理盐水。
每组使用八只动物。在第29天处死所有动物。根据Lunding,2015b测量以下读数。
·炎性细胞普遍浸润至支气管肺泡腔
·通过支气管肺泡灌洗(BAL)细胞的组织学分化确定嗜酸性粒细胞,中性粒细胞,和淋巴细胞的特异性浸润。
·CAST***(计算机辅助体视学工具箱)的杯状细胞增生,包括制作气道的显微图片。
·响应于乙酰甲胆碱的气道阻力以确定气道高反应性。
具体而言,使用来自支气管肺泡灌洗液(BALF)的细胞离心涂片(cyto-spinned)和迪夫快速染色(quick-diff-stained)的细胞对浸润支气管肺泡腔的炎性细胞亚群(嗜酸性粒细胞,巨噬细胞,中性粒细胞,淋巴细胞)进行量化。此外,从苏木精和伊红(HE)染色的肺/气道横截面记录了炎性细胞浸润。通过在用Buxco FinePoint RC单元机械通气的小鼠中记录乙酰甲胆碱(MCh)激发试验期间的气道阻力来评估AHR。在PAS(高碘酸-希夫)染色的气道横截面中,进行***的,均匀的随机取样,随后对气道中的粘液量和气道粘膜中产生粘液的杯状细胞进行体视学分析,以对粘液的过度产生进行量化。
结果
在第29天,即最终OVA气溶胶激发和达泮舒腈剂量的24小时后评估了过敏性气道炎症和粘液过度产生。图1示出了第29天的白细胞亚群(巨噬细胞,淋巴细胞,中性粒细胞,和嗜酸性粒细胞,从左到右)的总数。
在三次每日进行的OVA气溶胶激发的前一天以及与所述激发同时进行4次腹膜内注射来施用达泮舒腈(60mg/kg),导致BALF中嗜酸性粒细胞显著减少(图1)。与哮喘小鼠相比,用达泮舒腈治疗导致BALF中嗜酸性粒细胞减少大约60%(从21.96x104个细胞/ml至7.30x104个细胞/ml;****p<0.0001),中性粒细胞减少70%(从2.41x104个细胞/ml至0.70x104个细胞/ml;p<0.01),淋巴细胞减少32%(从0.80x104个细胞/ml至0.55x104个细胞/ml)。巨噬细胞数量没有显示出显著减少(图1)。
图2示出了哮喘小鼠肺组织中的炎性细胞数量与经达泮舒腈治疗的小鼠相比显著降低(**p<0.01)。y轴上的标签显示为“单位基底膜面积的炎性细胞浸润体积(μm3/μm2)”。使用带有计算机辅助体视学工具箱(CAST)***的显微镜对气道周围特定距离内的炎性细胞进行计数。这些计数与基底膜成比率设置,以在每个显微载玻片内标准化以避免载玻片依赖性差异。
图3示出了健康小鼠,哮喘小鼠,和经治疗小鼠的杯状细胞覆盖的上皮基底膜面积。与哮喘小鼠相比,达泮舒腈治疗的动物表现出覆盖气道粘膜的杯状细胞显著减少(从22.74%减少至17.67%,p<0.01),通过PAS染色的气道横截面的体视学进行量化。
图1-3的结果表明,在OVA诱发的过敏性气道炎症模型中,达泮舒腈治疗显著减轻过敏性气道炎症和粘液产生。
通过在第29天测量响应于100mg/mL乙酰甲胆碱的气道阻力确定了气道高反应性。结果示于图4。
响应于乙酰甲胆碱的气道阻力在哮喘小鼠中为5.61cm H2O·sec·ml-1,在达泮舒腈治疗的小鼠中为3.93cm H2O·sec·ml-1。与哮喘小鼠相比,达泮舒腈治疗使气道阻力降低了约60%。哮喘小鼠和经治疗小鼠之间****p<0.0001。健康动物的基线气道阻力为2.83cm H2O·sec·ml-1。
示例2 BALF中的细胞因子
细胞计数珠子阵列被用作评估示例1的BALF中IFN-γ,TNFα,IL-1β,IL-4,IL-5,IL-6,IL-10,IL-13,和IL17A)细胞因子浓度的方法。该阵列中的珠子涂有对多种细胞因子具有特异性的抗体,其中一些相关且已知受NLRP3信号传导的影响。所有被测量的细胞因子的浓度在哮喘小鼠和达泮舒腈治疗的小鼠之间均显示出有所降低。IL-1β和IL-6浓度在哮喘小鼠和达泮舒腈治疗的小鼠之间均显示出统计学上的显著降低(分别为p<0.001和p<0.05)。
示例3达泮舒腈治疗(口服)降低了小鼠的过敏性气道炎症和气道阻力
小鼠模型的实验方案与示例1描述的实验方案相同,不同的是达泮舒腈通过食物口服施用。
从第22天开始,对已经致敏的小鼠随意喂食含有7.5g/kg达泮舒腈的食物颗粒,持续一周;第一次气溶胶激发在第26天。小鼠通常每天消耗约4g食物,导致对照组的每日剂量大约为0mg/kg/天,治疗组的每日剂量大约为1,000mg/kg/天。小鼠食物(chow)中这种食物颗粒浓度(食物中7.5g/kg达泮舒腈)导致血液水平与口服剂量为1,000mg/天的达泮舒腈进行治疗的人的血液水平几乎相同(40μg/mL血液水平;Marchetti 2018b)。
假致敏的OVA激发的小鼠用作健康对照(健康)。OVA致敏的OVA激发的哮喘对照(哮喘)被喂食不含达泮舒腈的对照食物颗粒。
与哮喘小鼠相比,用达泮舒腈(食物)治疗导致BALF中嗜酸性粒细胞减少大约75%(从15.93x104个细胞/ml减少至3.77x104个细胞/ml;p<0.0001),中性粒细胞减少大约75%(从1.74x104个细胞/ml减少至0.43x104个细胞/ml;p<0.05),淋巴细胞减少大约75%(从1.00x104个细胞/ml减少至0.26x104个细胞/ml,p<0.05)。巨噬细胞数量没有显示出显著减少(图5)。
图6示出了哮喘小鼠肺组织中的炎性细胞数量与经达泮舒腈治疗的小鼠相比显著降低(p<0.05)。y轴上的标签显示为“每基底膜面积的炎性细胞浸润体积(μm3/μm2)”。使用带有计算机辅助体视学工具箱(CAST)***的显微镜对气道周围特定距离内的炎性细胞进行计数。这些计数与基底膜成比率设置,以在每个显微载玻片内标准化以避免载玻片依赖性差异。
与哮喘小鼠相比,经达泮舒腈治疗的小鼠还表现出覆盖气道粘膜的杯状细胞的显著减少(-29%;从15.75%减少至11.16%),通过PAS染色的气道横截面的体视学进行量化。(数据未示出)。
与假治疗的哮喘对照相比,响应于MCh的经达泮舒腈治疗的动物的气道阻力显著降低,显示在100mg/mL MCh时降低大约60%(从4.57cm H2O.s/mL降低至3.38cm H2O.s/mL)(图7)。哮喘小鼠和经治疗小鼠之间**p<0.01。在100mg/mL MCh时,健康动物的基线气道阻力为2.58cm H2O.s/mL。
结果表明,通过食物摄入达泮舒腈的治疗显著减轻过敏性气道炎症。
参考文献
Lunding L,Webering S,Vock C,et al.IL-37requires IL-18Ra and SIGIRR/IL-1R8 to diminish allergic airway inflammation in mice.A llergy 2015a Apr;70(4):366-73.Lunding LP,Webering S,Vock C,et al.Poly(inosinic-cytidylic)acid-triggered exacerbation of experimental asthma depends on IL-17A produced byNK cells.J Immunol 2015b;194:5615-5625.
Marchetti C,Swartzwelter B,Koenders MI,et al.The NLRP3 InflammasomeInhibitor OLT1177TM Suppresses Joint Inflammation in Murine Models of AcuteArthritis.Arthritis Research and Therapy 2018b;20:169.
Sel S,Wegmann M,Dicke T,et al.Effective prevention and therapy ofexperimental allergic asthma using a GATA-3-specific DNAzyme.JAllergy ClinImmunol 2008;121:910-916.e5.
Wegmann M,Fehrenbach H,Held T,et al.Involvement of distal airways ina chronic model of experimental asthma.Clin Exp Allergy 2005Oct;35(10):1263-71.Wegmann M,R,Sel S,et al.Effects of a low-molecular-weight CCR-3antagonist on chronic experimental asthma.Am J Respir Cell Molec Bio 2007;36(1):61-7.
现在以如此全面,清晰,简明,和准确的术语描述本技术以及制造和使用其的方式和过程,以至于本技术所属领域的任何技术人员能够制造和使用本技术。应当理解,前面描述了本技术的优选实施例,在不脱离如权利要求所述的本发明范围的情况下可以对其进行修改。为了明确指出并清楚地要求保护被视为发明的主题,以下权利要求对说明书进行了总结。
Claims (4)
1.达泮舒腈在制备用于治疗哮喘的药物中的用途,其中,达泮舒腈以有效治疗哮喘的量被口服施用于有需要的受试者。
2.根据权利要求1所述的用途,其中,所述用于治疗哮喘的药物减轻气道炎症,降低气道高反应性,改善肺功能,和/或减轻哮喘症状。
3.根据权利要求1所述的用途,其中,所述治疗是治疗性治疗,当所述受试者表现出哮喘的临床体征和/或症状时向所述受试者施用达泮舒腈。
4.根据权利要求1所述的用途,其中,所述治疗是预防性治疗,在哮喘发作之前向所述受试者施用达泮舒腈。
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Blockade of the NLRP3/Caspase-1 Axis Ameliorates Airway Neutrophilic Inflammation in a Toluene Disocyanate-Induced Murine Asthma Model;CHEN SHUYU ET AL;TOXICOLOGICAL SCIENCES;第170卷(第2期);462-475 * |
OLT1177, a beta-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation;MARCHETTI et al;PNAS;第115卷(第7期);E1530-E1539 * |
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