CN1449285A - Il-8受体拮抗剂在治疗病毒感染中的应用 - Google Patents
Il-8受体拮抗剂在治疗病毒感染中的应用 Download PDFInfo
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Abstract
本发明涉及IL-8受体拮抗剂在治疗人病毒感染以及相关加重症状中的新用途。
Description
发明领域
本发明涉及IL-8、GROα、GROβ、GROγ、NAP-2和ENA-78调节剂在治疗病毒感染中的应用。
发明背景
人鼻病毒(HRV)是普通感冒的最常见诱因,它日益与更为严重的后遗症相关,这些后遗症包括哮喘、慢性支气管炎、COPD、中耳炎和鼻窦炎的加重。最近公布的对成人和青少年进行的研究(采用PCR辅助病毒检测)表明,高达50-80%的哮喘加重与上呼吸道病毒感染相关,并且鼻病毒是最常见的感冒病毒。
HRV能感染鼻上皮细胞。最近的证据表明病毒也可感染支气管上皮组织。在感染后的24小时内会出现前驱感冒症状,2至5天时最严重,在7-14天之内消退。然而,这种效应对一些个体的影响时间更长。当病毒清除后,症状往往还存在。据信,这些症状是更多地由宿主对感染的反应而引起的,而非急性细胞毒素效应所致,这是因为仅有小部分的上呼吸道上皮细胞被证实感染,受损的上皮细胞极少。在感染了鼻病毒的正常个体中发现其鼻内的激肽、IL-1、IL-8、IL6、IL-11和嗜中性白细胞水平增加。最近的几项研究已经证实了鼻分泌物中IL-8浓度与局部骨髓过氧化物酶水平以及症状严重性之间的相关性。IL-1和IL-6的鼻内浓度也与症状的严重性相关。实验性鼻病毒感染也可导致增强型直接和晚期变态反应,并可增加T淋巴细胞和嗜曙红细胞对下气道的浸润。在特异性和哮喘中,这些效应会持续至感染后的2个月。已经证明人支气管上皮细胞系在对鼻病毒感染的应答中可产生IL-1、IL-6,IL-8、IL-11和GM-CSF。因此,鼻病毒感染的上皮细胞早期产生的细胞因子会引起嗜中性白细胞、T细胞和活化嗜曙红细胞触发补充到上和下气道中。
另外,在对其他呼吸病毒(流感、呼吸道合胞体病毒)感染的应答中也会产生IL-1、IL-6和IL-8,所述病毒可诱导普通感冒和相关后遗症。
白介素-8(IL-8)有许多不同的名称,例如嗜中性诱引剂/活化蛋白-1(NAP-1)、单核细胞衍生的嗜中性白细胞趋化因子(MDNCF)、嗜中性白细胞活化因子(NAF)和T细胞淋巴细胞趋化因子。白介素-8是嗜中性白细胞、嗜碱细胞和T细胞亚型的化学引诱物。它可由许多有核细胞(包括接触TNF、IL-1α、IL-1β或LPS的巨噬细胞、纤维母细胞、内皮细胞和上皮细胞产生,并可由接触LPS或趋化因子例如FMLP的嗜中性白细胞本身产生。参见M.Baggiolini等,J.Clin.Invest.84,1045(1989);J.Schroder等,J.Immunol.139,3474(1987)和J.Immunol.144,2223(1990);Strieter等,Science 243,1467(1989)和J.Biol.Chem.264,10621(1989);Cassatella等,J.Immunol.148,3216(1992)。
GROα、Groβ、GROγ和NAP-2也属于趋化因子家族。与IL-8一样,这些趋化因子也具有许多不同的名称。例如GROα、β、γ分别被称为MGSAα、β、γ(黑素瘤生长刺激活性),参见Richmond等,J.Cell Physiology 129,375(1986)和Chang等,J.Immunol 148,451(1992)。在CXC基序之前直接具有ELR基序的所有α-家族趋化因子均可与IL-8B受体(CXCR2)结合。
IL-8、GROα、Groβ、GROγ、NAP-2和ENA-78可在体外刺激多种功能。它们对嗜中性白细胞均表现出化学引诱物特性,而IL-8和GROα已证实具有T-淋巴细胞和嗜碱细胞趋化活性。另外,IL-8可诱导组胺从正常和特异反应性个体的嗜碱细胞中释放。GROα和IL-8还可诱导嗜中性白细胞的溶菌酶释放和呼吸爆发。IL-8还可增加Mac-1(CD1 lb/CD18)在嗜中性白细胞上的表面表达而没有全程合成蛋白质。
在体外,IL-8、GROα、Groβ、GROγ和NAP-2可通过结合并活化七跨膜受体、G蛋白结合家族,特别是IL-8受体、尤其是IL-8β受体(CXCR2)结合,而诱导嗜中性白细胞的形态变化、趋化性、颗粒释放和呼吸爆发。Thomas等,J.Biol.Chem.266,14839(1991);和Holmes等,Science253,1278(1991)
已经表征了两种高亲合性的人IL-8受体(77%同源性):IL-8RA,它仅与IL-8以高亲合性结合,和IL-8RB,它与IL-8以及GROα、Groβ、GROγ和NAP-2具有高亲合性。参见Holmes等,同上述文献;Murphy等,Science 253,1280(1991);Lee等,J.Biol.Chem.267,16283(1992);LaRosa等,J.Biol.Chem.267,25402(1992);和Gayle等,J.Biol.Chem.268,7283(1993)。
因病毒感染而对上皮细胞的生物化学进程所造成的干扰代表了IL-8受体拮抗剂的可行的新型治疗靶。本发明即涉及治疗这种治疗靶的新发现。
发明概述
本发明提供治疗趋化因子介导疾病的方法,其中趋化因子是与IL-8A或B受体结合的趋化因子,该方法包括给药有效量IL-8受体拮抗剂或其药用盐。本发明还涉及IL-8受体拮抗剂在治疗(包括预防和防止/降低潜在病情的严重性)病毒感染中的应用,所述病毒包括但不限于:人鼻病毒、肠道病毒、冠状病毒、流感病毒、副流感病毒、呼吸道合胞体病毒和腺病毒,该方法包括将有效量的IL-8受体拮抗剂给予需要这种治疗的人。发明详述
IL-8和其他细胞因子对多种细胞和组织均有影响,这些细胞因子以及其他白细胞衍生的细胞因子是重要和决定性的炎性介体,它们可引起许多病毒感染症状。抑制这些细胞因子有益于控制、减少和减轻大多数这些呼吸病毒感染症状。此外,本发明涉及治疗人因病毒感染所致的症状,所述病毒包括人鼻病毒、其他肠道病毒、冠状病毒、疱疹病毒、流感病毒、副流感病毒、呼吸道合胞体病毒或腺病毒。此外,本发明涉及呼吸病毒感染,它可加重潜在慢性病状例如哮喘、慢性支气管炎、慢性阻塞性肺病、中耳炎和鼻窦炎。应当指出的是,这里治疗的呼吸道病毒感染与继发性细菌感染(例如中耳炎、鼻窦炎或肺炎)有关。
本发明将证实IL-8受体拮抗剂可用来治疗与呼吸病毒感染相关的症状,它能防止/减轻潜在症状(包括哮喘和中耳炎、COPD、鼻窦炎、慢性支气管炎等)加重的程度。
适宜的IL-8抑制剂是本领域已知的,而且测定IL-8抑制的分析法也可很容易获得。例如,参见美国专利5886044,5780483,6005008,5929250,6015908;5919776;美国专利申请09/111663,09/125279,09/240354,09/202570,09/202586,09/202569,09/202568,09/230120,09/230290,09/230952,09/230977,09/230981,09/230980,09/242187,09/341378,09/341382,09/341262,09/463673,09/508039,09/486986;WO99/65310,WO0012489,WO0009511,WO9942464,WO9942463,WO9942461,WO00/05216,WO99/36069,WO99/36070,WO00/06557;PCT/US99/23776,PCT/US99/29940;美国临时申请60/134728,60/136666,60/136665,60/136717,60/136667,60/139675,60/139680,60/139678,60/139673,60/140024,60/139677,60/139674,60/140025,60/145756,60/164350,60/186239,60/186183,60/186182,60/188410,60/188243,60/189176,60/189175,60/189848,60/192132,或60/196022。
IL-8受体拮抗剂也可与第二治疗剂联用。所述第二种治疗剂可以是抗病毒剂,例如利巴韦林、amantidine、rimantidine、relenza、tamiflu、BTA 188、RWJ-270210(BCX1812)、sICAM-1、tICAM453、Pleconaril或AG 7088;也可是抗组胺剂,例如苯海拉明、扑尔敏及其盐、溴苯吡丙胺及其盐等,减充血剂,例如N-去甲麻黄碱及其盐、假麻黄碱及其盐;甾族化合物,例如地塞米松、泼尼松或氢化泼尼松等;各种抗生素,例如喹诺酮类、头孢菌素类、p-内酰胺酶抑制剂等;抗炎剂,例如CSAIDS、COX-1或COX-2抑制剂、ASA、或吲哚美辛等。
附图简述
附图1-为CXCR2拮抗剂X对RV或Groβ诱导的人嗜中性白细胞中钙迁移(mobilization)的抑制。
附图2-为CXCR2拮抗剂X对RV-诱导的人嗜中性白细胞趋化性的抑制
附图3-为RV、Groα、Groβ和groβ-T诱导的嗜中性白细胞中钙迁移。
治疗方法
本发明IL-8受体拮抗剂或其药用盐可用来制造用于预防性或治疗性治疗人或其他哺乳动物病毒感染症候或后遗症的药物,所述症候或后遗症是因哺乳动物细胞产生过度或失调的IL-8细胞因子而加重或所引起的,所述哺乳动物细胞例如但不限于单核细胞和/或巨噬细胞,或与IL-8A或B受体(也称为I型或II型受体)结合的其他趋化因子。
因此,本发明提供了治疗病毒感染的方法,其中趋化因子是与IL-8A或B受体结合的趋化因子,该方法包括给药有效量的本发明抑制剂或其药用盐。特别地,趋化因子为IL-8、GROα、Groβ、GROγ、NAP-2或ENA-78。
为了使本发明IL-8受体拮抗剂或其药用盐能用于治疗,通常可采用标准制药方法将其配制成药物组合物。因此,本发明还涉及药物组合物,其中包括有效的、非毒性量的本发明IL-8受体拮抗剂和药用载体或稀释剂。
本发明IL-8受体拮抗剂、及其药用盐和药物组合物可方便地以任何常规给药途径进行给药,例如口服、局部、经颊(bucolally)、非肠道或经吸入。它们可以常规剂型给药,按照常规方法将本发明化合物与标准药用载体混合,即可制得所述剂型。它们也可与另一已知的治疗活性化合物以常规剂型联合给药。这些方法包括混合、制粒和压制,或需要时将各成分溶解得到所需制剂。可以理解,所用的药用载体或稀释剂的形式以及特性将取决于与其混合的活性成分的用量、给药途径和其他已知因素。载体必须是“可接受的”,即能与制剂中的其他成分配伍并且对接受者无害。
所用的药用载体例如可以是固体或液体。示例性固体载体是乳糖、白土、蔗糖、滑石、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸等。示例性液体载体为糖浆、花生油、橄榄油、水等。同样地,载体或稀释剂还可包括本领域已知的延时材料,例如甘油单硬脂酸酯或甘油二硬酸酯或与蜡的混合物。
可以采用各种药物形式。如果采用固体载体,则制剂可以经压片、或者置于硬明胶胶囊中的粉末或微丸形式,或者是锭剂或糖锭形式。固体载体的用量可以有较大的变化,但是优选约为25mg-1g。当采用液体载体时,制剂可以是糖浆剂、乳剂、软明胶胶囊、无菌注射液例如安瓿剂或非水性液体混悬剂。
本发明拮抗剂可局部给药,即非全身性给药。这包括将本发明化合物外部给药到表皮或口腔,以及将化合物滴注到耳、眼和鼻中,从而使化合物不至于明显地进入血流。相反地,全身性给药是指经口、静脉内、腹膜内和肌内给药。
适于局部给药的制剂包括适于穿透皮肤炎症部位的液体或半液体制剂,例如搽剂、洗剂、乳膏、软膏、或糊剂,和适于耳或鼻给药的滴剂,适于吸入给药的溶液或混悬剂。对于局部给药,活性成分可以占制剂重量的0.001%-10%w/w,例如1%-2%。尽管可高达制剂的10%w/w,但是优选低于5%w/w,更优选为0.1%-1%w/w。
本发明洗剂包括那些适于皮肤或眼部给药的制剂。眼用洗剂可包括无菌水性溶液,其中任选含有杀菌剂,并且可按类似于配制滴剂的方法配制。皮肤用的洗剂或搽剂也可包括用来加速皮肤干燥和冷却的试剂,例如醇或丙酮,和/或增湿剂例如甘油或油类例如蓖麻油或花生油。
本发明乳膏、软膏或糊剂是供外用的活性成分的半固体制剂。借助于适宜的机械,将单独的或在水性或非-水性液体中的溶液或混悬液中的细碎和粉末形式的活性成分与油脂或非油脂基质混合,即可制得上述制剂。基质可以包括烃类例如硬、软或液体石蜡、甘油、蜂蜡、金属皂;胶浆;天然来源的油例如杏仁油、玉米油、花生油、蓖麻油或橄榄油;羊毛脂或其衍生物或脂肪酸例如硬脂酸或油酸以及醇例如丙二醇或聚乙二醇。制剂中可掺入任何适宜的表面活性剂,例如阴离子、阳离子或非离子表面活性剂例如脱水山梨醇酯或其聚氧化乙烯衍生物。还可还有助悬剂,例如天然胶、纤维素衍生物或无机材料例如硅石,和其他成分例如羊毛脂。
本发明滴剂可以包括无菌水性或油性溶液或混悬剂,将活性成分溶于适宜含水溶液中即可制得,所述溶液中含有杀菌剂和/或杀真菌剂和/或任何其他适宜的防腐剂和优选包括表面活性剂。然后,经滤过将所得溶液澄清,移至适宜的容器中,然后密封并经高压灭菌法或于98-100保持半小时灭菌。或者,将溶液经滤过灭菌并在无菌操作下移至容器中。适用于滴剂的示例性杀菌剂和杀真菌剂是硝酸苯汞或醋酸苯汞(0.002%)、氯苄烷铵(0.01%)和醋酸洗必泰(0.01%)。用于制备油性溶液的适宜溶剂包括甘油、稀醇和丙二醇。
本发明拮抗剂可经非肠道给药,即经静脉内、肌内、皮下、鼻内、直肠内、阴道内、或腹膜内给药,通常优选皮下和肌内的非肠道给药。采用常规技术,可配制用于给药的这类适当剂型。本发明拮抗剂也可经吸入给药,即经鼻内和口吸入给药。采用常规技术,可配制用于给药的合适剂型例如气雾剂或计量吸入剂。
至于在此公开的本发明拮抗剂的所有使用方法,每日口服剂量方案优选约为0.0-80mg/kg体重。每日非肠道剂量方案约为0.00-80mg/kg体重。每日局部剂量方案优选为0.1mg-150mg(每日给药1-4次、优选2或3次)。每日吸入剂量方案优选约为0.01mg/kg-1mg/kg/天。本领域技术人员可以理解,本发明拮抗剂或其药用盐的最佳用量和各剂量的给药间隔取决于所治疗病症的性质和程度、剂型、给药途径和部位以及所治疗的具体患者,所述最佳方案可采用常规技术确定。本领域技术人员还可以理解,最佳的疗程即本发明化合物或其药用盐在指定天数内每天给药的次数,可由本领域技术人员根据常规的疗程确定试验来确定。
现将参考以下生物学实施例描述本发明,这些实施例旨在说明,对本发明范围并无限制。生物学实施例
通过以下体外试验,测定了本发明化合物的IL-8和GROα的趋化因子抑作用:
受体结合试验:[125I]IL-8(人重组体)来自Amersham公司,ArlingtonHeights,IL,其比活性为2000 Ci/mmol。GROα来自NEN-New England Nuclear公司。所有其他化学品均为分析纯。按在先所述(Holmes,等,Science,1991,253,1278),用中国仓鼠卵巢细胞分别表达高水平的重组人IL-8α型和β受体。按一种在先所述的方法(Haour,等,J.Biol.Chem.,249 pp 2195-2205(1974))将中国仓鼠卵巢细胞匀化。不同的是,匀化缓冲液改为10mM Tris-HCL、1mMMgSO4、0.5mM EDTA(乙二胺四乙酸)、1mM PMSF(α-甲苯璜酰氟)、0.5mg/L亮肽素,pH 7.5。采用牛血清白蛋白为标准,用Pierce Co.公司的微分析试剂盒测定膜蛋白质浓度。所有试验均在96-孔微平板中完成。每一反应混合物含有在20mM Bis-Trispropane和0.4mM Tris HCl缓冲液中(pH 8.0)的125IIL-8(0.25nM)或125I GROα和0.5pg/mL的IL-8Rα或1.0pg/mL的IL-8Rβ膜,所述缓冲液中1.2mM MgSO4、0.1mM EDTA、25mM Na和0.03%CHAPS。此外,加入待试药物或化合物(预先溶于DMSO中,其终浓度为0.01nM-100μM)。加入125I-IL-8启动试验。室温反应1小时后,用Tomtec 96-孔采集器将平板收采集到玻璃纤维滤垫上(已用1%聚乙烯亚胺/0.5%BSA阻断),用25mM NaCl、10.mM TrisHCl、1mM MgSO4、0.5mM EDTA、0.03%CHAPS(pH 7.4)洗涤3次,然后干燥滤器,用Betuplate液体闪烁计数器计数。重组体IL-8Rα(或I型)受体在此称为非允许受体,而重组IL-8Rβ(或II型)受体称为允许受体。趋化性试验
按照《免疫学通用方法》(
Current Protocols In Immunology),I卷,增刊1,6.12.3.单元中描述的方法,用嗜中性白细胞趋化性试验测定这些化合物的体外抑制特性,其全部公开内容在此引入作为参考。如同《免疫学通用方法》卷I,增刊1 7.23.1单元中的描述,从人血中分离出嗜中性白细胞,其全部公开内容在此引入作为参考。将化学引诱物IL-8、GROα、GROβ、GROγ和NAP-2置于48孔多孔室(Neuro Probe,Cabin John,MD)的底部室(浓度为0.1-100nM)。两个室间用5uM聚碳酸酯滤器隔开。当检测本发明化合物时,在将细胞加到上部室之前,将化合物与细胞(0.001-1000nM)混合。在含5%CO2的加湿恒温箱中,于约37保温约45-90分钟。保温结束时,除去聚碳酸酯膜,洗涤顶侧面,然后用Diff Quick染色法(Baxter Products,McGaw Park,IL,USA)对膜进行染色。采用显微镜,对已趋化成趋化因子的细胞用肉眼计数。通常,每个试样计数4个区域,将这些数字平均得到已迁移细胞的平均数。每个试样试验三次,每一化合物重复至少4次。某些细胞(阳性对照细胞)中不加入化合物,这些细胞代表着细胞的最大趋化性反应。在需要阴性对照(未刺激的)的情况下,下部室中不加入趋化因子,阳性对照与阴性对照间的差异代表了细胞的趋化活性。弹性酶释放试验
测试了本发明化合物抑制人嗜中性白细胞释放弹性酶的能力。如同《免疫学通用方法》卷I,增刊1 7.23.1单元中的描述,从人血中分离出嗜中性白细胞。将悬浮于林格液(NaCl 118、KCl 4.56、NaHCO3 25、KH2PO4 1.03、葡萄糖11.1、HEPES 5mM,pH 7.4)中的PMNs(0.88×106细胞)置于体积为50μl的96孔平板的每一孔中。向平板中加入体积为50μl的待试化合物(0.001-1000nM)、体积为50μl的细胞松弛素B(20ug/ml)和体积为50μl的林格缓冲液。在加入IL-8、GROα、GROβ、GROγ或NAP-2(终浓度为0.01-1000nM)之前,将这些细胞加热(37,5%CO2,95%相对湿度)5分钟。反应进行45分钟,然后将96孔平板离心(800xg 5分钟),取出100μl上清液。将该上清液加至另一96孔平板中,然后加入溶于磷酸缓冲盐水中的人工弹性酶底物(终浓度为6ug/ml)(MeOSuc-Ala-Ala-Pro-Val-AMC,Nova Biochem公司,La Jolla,CA)。按照Nakajima等J.Biol.Chem.254 4027(1979)中的方法,立即将平板置于荧光96孔平板阅读器(Cytofluor 2350,Millipore,Bedford,MA)上,并以3分钟的间隔收集数据。测定MeOSuc-Ala-Ala-Pro-Val-AMC的降解率,可计算出从PMNs中释放的弹性酶量。鼻病毒方法
细胞系和鼻病毒血清型39购自美国典型培养物保藏中心(ATCC)。按照ATCC提供的指导,采用购自Clonetics公司的BEGM(支气管上皮生长培养基)培养BEAS-2B细胞。将用于病毒检测和效价的HELA细胞培养物保持在Eagle氏最低要求标准培养基(含有10%胎牛血清、2mM 1-谷氨酰胺和10mM HEPES缓冲剂(MEM))中。
在这些研究中,采用了Subauste等在上述文献中报道的体外用鼻病毒感染人支气管上皮细胞的改良方法。在用鼻病毒感染之前,将BEAS-2B细胞(2×105/孔)在胶原涂层的孔中培养24小时。将鼻病毒血清型39加至细胞培养物中,于34保温1小时,然后用新鲜培养基替换接种物,再于34将培养物保温72小时。感染72小时后收集上清液,采用市售试剂盒(R&DSystems)经ELISA法测定细胞因子蛋白质的浓度。在HELA细胞培养物中,采用微量滴定分析法(Subauste等,同上述文献,1995),测定培养物上清液中的病毒产量。在感染30分钟之前,向经IL-8抑制剂处理的培养物中加入药物。在DMSO(10mM药物)中配制化合物贮备液并与-20贮存。
为了检测IL-8R的抑制,将培养物置于基础培养基中保温,所述培养基中不含生长因子和添加剂,以减少内源性活化的IL-8水平。加入鼻病毒后,在不同时间点采集上清液并浓缩。浓缩物在Superose 6柱上分级。采用Amicon浓缩器(截留摩尔量为5,000),将上清液浓缩(大于50倍)。向Superose6尺寸分级柱一次进样(0.5ml),分级柱用单一流速(0.2ml/min)洗脱。收集0.5ml级分,供在新鲜分离的人PMN(负载FURA-2)中测定Ca2+迁移活性。结果:
表征RV感染的BEAS-2B人上皮细胞产生的趋化因子
在静止(resting)条件下,人BEAS-2B人上皮细胞可产生少量的至少3种已知人趋化因子:GROα、IL-8和ENA78。与静止条件下的产量相比,当这些细胞被鼻病毒感染时,这3种ELR趋化因子的产量提高6.6-20倍(表1)。
表1.在静止和感染的条件下BEAS-2B上皮细胞产生的ELR趋化因子(n=6)
处理 | GROα(pg/ml) | IL-8(pg/ml) | ENA-78(pg/ml) |
对照 | 1568±402 | 143±86 | 164±33 |
HRV-39 | 12135±3599 | 2870±645 | 1083±194 |
当将HRV-39感染的上皮细胞上清液在Superose 6柱上进行尺寸排阻分级时,用人嗜中性白细胞(图III)或经CXCR1或CXCR2受体转染的细胞系测定,可得到Ca2+迁移活性单峰。在相同级分(洗脱趋化因子IL-8、ENA78和Groα)中,均出现Ca2+在嗜中性白细胞中的迁移。
为了确定未经ELISA试剂盒分析的HRV-39感染的BEAS-2B是否会产生其他趋化因子,在能表达多种趋化因子受体(包括CCR1、CCR2、CCR3和CCR5)的其他新鲜分离的人周围细胞中,对BEAS-2B上清液进行了测定。当采用负载Fura-2的嗜曙红细胞或周围血液单核细胞(PBLs),对衍生于BEAS-2B上皮细胞的上述活性级分进行Ca2+迁移测定时,没有级分使Ca2+迁移。这表明除IL-8、Groα和ENA-78之外,并不存在足以促进Ca2+迁移的有效浓度的趋化因子。
为了确定对其他PMN活化的趋化因子的潜在性以及L-8经CXCR2活化PMNs的可能性,我们在负载Fura-2的PMNs中测定了IL-8受体拮抗剂抑制Ca2+迁移的能力,所述迁移由Groβ、浓缩BEAS-2B上清液或经Superose6柱分离得到的活性级分所诱导。如附图I所示,化合物-X剂量依赖性地完全抑制了含有趋化因子的RV浓缩上清液和级分(由Superose 6柱得到),其IC50为1.7-2nM。该IC50与单独Groβ得到的IC50(IC50=5nM)相似,这表明浓缩物或级分中的所有Ca2+迁移活性是通过CXCR2受体起作用。
为了确定RV上清液是否仅通过CXCR2受体来起作用,我们测定了许多选择性CXCR2拮抗剂与其抑制Ca2+迁移(由浓缩RV上清液和Groβ诱导)的能力之间的等级相关性。CXCR2拮抗剂趋异倾向(divergent set)与其抑制RV和Groβ所致Ca2+迁移的能力之间具有良好的等级相关性,这表明RV上清液Ca2+迁移活性仅通过PMNs上的CXCR2受体起作用。
在浓缩和分级的RV试样中,也测定了对PMN趋化性的抑制。特定CXCR2拮抗剂对趋化性的抑制如附图II所示。
这些结果证实,BEAS-2B细胞产生了多种ELR趋化因子,这些趋化因子通过CXCR2受体而起作用并且可被选择性CXCR2拮抗剂所阻断。尽管上清液中也存在IL-8,但是它完全被CXCR2拮抗剂阻断。与Groα相比,IL-8的水平较低,是不大可能起作用的。
本说明书中提及的所有出版物,包括但不限于专利或专利申请,均在此引用作为参考,就好象每一出版物均特定和独立地被引入作为参考。
以上说明完全公开了本发明所包括的优选实施方案。对在此具体公开的实施方案所作的修饰或改进均在下面权利要求书的范围之内。无需进一步说明,应当认为本领域技术人员利用上述说明能充分实现本发明。在此所述的实施例仅仅是示例性的,对本发明范围并无任何限定。下面将限定要求保护的专有权或特权的本发明实施方案。
Claims (13)
1.治疗病毒感染所致普通感冒症候的方法,所述病毒包括人鼻病毒、其他肠道病毒、疱疹病毒、冠状病毒、流感病毒、副流感病毒、呼吸道合胞体病毒或腺病毒,该方法包括将有效量的IL-8受体拮抗剂给予需要这种治疗的人。
2.根据权利要求1的方法,其中所述呼吸病毒感染使哮喘加重。
3.根据权利要求1的方法,其中所述呼吸病毒感染使慢性支气管炎加重。
4.根据权利要求1的方法,其中所述呼吸病毒感染使慢性阻塞性肺部疾病加重。
5.根据权利要求1的方法,其中所述呼吸病毒感染使中耳炎加重。
6.根据权利要求1的方法,其中所述呼吸病毒感染使鼻窦炎加重。
7.根据权利要求1的方法,其中所述呼吸病毒感染与另一细菌感染例如中耳炎、鼻窦炎或肺炎相关。
8.根据权利要求1-7任一的方法,其中IL-8受体拮抗剂与第二种治疗剂联用。
9.根据权利要求1的方法,其中第二种治疗剂选自抗病毒剂、抗组胺、减充血剂、甾类化合物、抗生素和抗炎剂。
10.根据权利要求1-9任一的方法,其中经口、经颊、局部(鼻内)或经吸入(气雾剂),或经局部和经吸入给药治疗剂。
11.根据权利要求10的方法,其中所述化合物与第二种治疗剂联用。
12.根据权利要求11的方法,其中第二种治疗剂选自抗病毒剂;抗组胺;减充血剂;甾类化合物;抗生素;和抗炎剂。
13.根据权利要求1的方法,其中IL-8受体拮抗剂选自以下专利或申请披露的化合物:美国专利5886044,5780483,6005008,5929250,6015908,或5919776;美国申请09/111663,09/125279,09/240354,09/202570,09/202586,09/202569,09/202568,09/230120,09/230290,09/230952,09/230977,09/230981,09/230980,09/242187,09/341378,09/341382,09/341262,09/463673,09/508039,或09/486986;WO99/65310,WO0012489,WO0009511,WO9942464,WO9942463,WO9942461,WO00/05216,WO99/36069,WO99/36070,或WO00/06557;PCT/US99/23776,或PCT/US99/29940;美国临时申请60/134728,60/136666,60/136665,60/136717,60/136667,60/139675,60/139680,60/139678,60/139673,60/140024,60/139677,60/139674,60/140025,60/145756,60/164350,60/186239,60/186183,60/186182,60/188410,60/188243,60/189176,60/189175,60/189848,60/192132,或60/196022。
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