CN1901892A - 使用ice抑制剂治疗感染疾病 - Google Patents
使用ice抑制剂治疗感染疾病 Download PDFInfo
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- CN1901892A CN1901892A CNA2004800398687A CN200480039868A CN1901892A CN 1901892 A CN1901892 A CN 1901892A CN A2004800398687 A CNA2004800398687 A CN A2004800398687A CN 200480039868 A CN200480039868 A CN 200480039868A CN 1901892 A CN1901892 A CN 1901892A
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- chemical compound
- ice
- infection
- ice inhibitor
- ciprofloxacin
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Abstract
本发明涉及通过给予ICE抑制剂治疗感染和其它疾病,特别是眼睛的方法。本发明还涉及通过给予ICE抑制剂治疗眼睛的损伤、变态反应、化学刺激、或烧伤的方法。
Description
技术领域
本发明涉及使用ICE抑制剂治疗感染和其它疾病和病症的方法及组合物。
背景技术
绿脓假单胞菌(P.aeruginosa)角膜炎是一种威胁视力的角膜疾病,占所报道的与接触镜片(隐形眼镜)有关的微生物感染病例的约3/4(Liesegang,1997)。如不积极治疗,疾病会迅速发展,引起角膜溃疡且可潜在导致由于角膜瘢痕所致的永久性视力损失(Laibson,1972)。假单胞菌角膜炎过程中的组织损害可由于多种微生物(Engel等人,1998;Kernacki等人,1995)和宿主-相关因素(Steuhl等人,1987;Steuhl等人,1989)而发生。然而,宿主炎性反应已在实验方面表现出对绿脓假单胞菌所致眼睛感染的结果起重要作用(Hazlett,2002;Huang等人,2002;Kernacki等人,2000;McClellan等人,2003;Rudner等人,2000;Thakur等人,2002;Xue等人,2003a;Xue等人,2003b)。
细菌性角膜炎的治疗是要除去感染性生物并抑制宿主的破坏性炎症反应。通常,将在强化眼用溶液中使用氨基糖苷类和第三代头孢菌素的双重疗法(Baum和Barza,2000;Dart和Seal,1988;Guzek等人,1994)或使用氟喹诺酮的单一疗法(Leibowitz,1991;Parks等人,1993)用于治疗假单胞菌角膜炎。近来,抗生素(特别是氟喹诺酮)抗性绿脓假单胞菌菌株所致的顽固性细菌性角膜炎发生率的增加(Chaudhry等人,1999;Garg等人,1999;Kunimoto等人,1999;Landman等人,2002)受到重大关注且还可限制未来的治疗选择。
皮质类固醇是标准的抗炎药物疗法,用于治疗抗细菌疗法残余的炎症。目前,在细菌性角膜感染之后,仅把皮质类固醇用于眼用溶液中来抑制进行性炎性反应。然而,病原生物的鉴别和对抗细菌疗法的反应(或抗细菌敏感性)是关键的限制性因素,在开始皮质类固醇治疗之前必须加以考虑。还没有在细菌性角膜炎中确定地证实皮质类固醇对降低宿主介导的组织损害方面的(有益或有害)作用(Hobden等人,1993;Hobden等人,1992;Phillips等人,1983;Waterbury等人,1987;Wilhelmus,2002)。因此,皮质类固醇引起争议的作用和已经出现的绿脓假单胞菌对抗生素的抗性使有理由研制新的辅助治疗形式。
细胞因子(特别是IL-1β和TNF-α)是最佳的治疗靶,这是因为它们可引发并继续多种疾病。各种策略如可溶性受体、抗体、受体拮抗剂或抑制剂用于阻断细胞因子。这些特异性的、基于抗-细胞因子的疗法已经显示出可减轻许多慢性炎性或自身免疫疾病中的炎症且已由FDA批准人类使用(Bresnihan等人,1998;Mohler等人,1993;Nuki等人,2002;van Deventer,1999)。IL-1β在假单胞菌角膜炎发病机理中的重要性已在先前的研究中被证实(Rudner等人,2000;Thakur等人,2002;Xue等人,2003b)。IL-1β表达水平的持续升高与角膜疾病的严重程度有关,而水平降低(抗体中和或IL-1β受体抑制之后)导致疾病严重程度降低。
尽管广谱抗细菌剂有效,但是细菌性角膜炎仍然是限制视力的瘢痕形成和视觉损伤的主要原因,特别是在接触镜片(隐形眼镜)的使用者中(Poggio等人,1989;Schein等人,1989;Schein和Poggio,1990)。仅在美国就有超过3千万人使用接触镜片(Barr等人,2000),每天佩戴接触镜片的使用者中每2,500人中就有1人,且每年长期佩戴接触镜片的使用者中每500人中就有1人发展成细菌性角膜炎(Schein和Poggio,1990)。传统上,在获得培养物从而鉴别出病原生物之后,在角膜炎病例中迅速建立广谱抗细菌(常常是环丙沙星)疗法。虽然抗-微生物治疗常常能够使角膜无菌,但它不能确保澄明的视轴,这是由于残留的宿主衍生的炎症。这可能需要使用皮质类固醇来恢复角膜澄明。在一些情况下,皮质类固醇的使用可具有潜在不利的作用,包括延迟角膜伤口愈合(Leibowitz等人,1996;Singh,1985)。
因此,需要其它治疗感染,特别是眼睛感染中炎症的方法。
ICE,也称作天冬氨酸特异性半胱氨酸蛋白酶-1,是一种将IL-1β和IL-18的前体裂解成活性细胞因子的胞内蛋白酶(Akita等人,1997;Kuida等人,1995)。虽然其它蛋白酶(包括细菌和宿主蛋白酶)可处理前-IL-1β,但ICE-缺陷(ICE-/-)小鼠已经显示不能在应答内毒素时释放成熟的IL-1β(Fantuzzi等人,1997;Li等人,1995)。
然而,ICE抑制剂还没有显示出可有效地治疗特定疾病,如细菌性角膜炎。因此,需要小分子ICE抑制剂来治疗感染,如细菌性角膜炎。
发明内容
本发明涉及使用ICE抑制剂治疗感染和相关疾病的方法。本发明还涉及通过给予ICE抑制剂治疗眼睛的损伤、变态反应、化学刺激、或烧伤的方法。
申请人已经在由绿脓假单胞菌或环丙沙星抗性绿脓假单胞菌菌株的临床分离物诱导的实验性角膜感染中证实了ICE抑制剂的功效。采用临床得分、病理组织学、MPO活性、细菌平板计数和ELISA分析来评价在绿脓假单胞菌菌株19660感染角膜后的C57BL/6(B6)小鼠中,使用ICE抑制剂与安慰剂+/-环丙沙星相比治疗的功效(p.i.第18小时)。在ICE抑制剂与安慰剂+/-环丙沙星相比治疗的小鼠中,感染后(p.i.)第3、5和7天的临床得分明显降低。炎性反应的降低还可通过在用ICE抑制剂与安慰剂+/-环丙沙星治疗相比的小鼠角膜中,p.i.第7天时,MPO活性和IL-1β及MIP-2蛋白水平的降低加以证实。
在用ICE抑制剂与没有环丙沙星的安慰剂治疗相比的小鼠中,在p.i.第7天时的角膜中,细菌负荷量同样降低。ICE抑制剂还可降低由临床分离物-1025或环丙沙星抗性绿脓假单胞菌菌株诱导的角膜感染后的临床得分。ICE抑制剂单独或与环丙沙星联合给药可显著降低角膜疾病的严重程度并显示出细菌感染后的宿主炎性反应可由靶向ICE和IL-1β的治疗策略成功控制。
本发明包括ICE/天冬氨酸特异性半胱氨酸蛋白酶-1的用途,无论对ICE/天冬氨酸特异性半胱氨酸蛋白酶-1是选择性的,还是广泛作用于其它天冬氨酸特异性半胱氨酸蛋白酶(例如,2-14)。该治疗,通过抑制ICE和抑制IL-1β产生,可减轻感染的症状和/或减少感染。在优选实施方案中,该抑制剂是选择性ICE抑制剂。
本发明还涉及鉴别用于治疗这些疾病的药剂的方法。
本发明还涉及用于制备组合物的方法和实践本发明方法的试剂盒。
发明详述
本发明提供了通过给予ICE抑制剂治疗感染,特别是眼睛感染的方法。
申请人已证实单独或与抗细菌剂联合使用ICE抑制剂可非常有效地治疗动物模型的角膜炎。
具体而言,申请人已证实ICE抑制剂能够通过调节宿主炎性反应,以及抑制剂限制细菌生长的能力而控制角膜降解,这可能是由于有效杀死了炎性降低环境中的细菌。数据提供的证据表明,内源性IL-1β活性的降低可通过组织-损害宿主衍生的炎性反应的负调节而提高宿主抗绿脓假单胞菌。
因此,本发明其中一个实施方案提供了一种调节宿主炎性反应的治疗策略。
申请人意外地证实了ICE抑制剂不仅可减轻模型的炎症,还可降低细菌生长。不受理论的束缚,申请人相信ICE抑制剂可减少细菌生长,这在一定程度上是由于细菌不能在损害降低的角膜中散播。
本发明的另一优点在于ICE抑制剂可减轻症状如与各种感染有关的疼痛、骚痒和不适。有利的是,这些益处可通过使用单一化合物,而不是使用多种化合物(例如,抗细菌和抗炎剂)来实现。因此,本发明提供了预防、抑制、控制、终止、处理、或降低微生物感染的毒力和/或炎症和/或疼痛。在优选实施方案中,感染、炎症或疼痛位于眼睛中。
ICE抑制剂治疗的小鼠表现出与安慰剂治疗组相比,IL-1β和MIP-2(PMN的化学吸引剂)水平显著降低、PMN浸润和细菌负荷量降低。ICE抑制剂治疗组的病理组织学检查表明完整角膜上皮的浸润细胞显著减少且支持了临床得分的观察结果。向局部用抗细菌剂(环丙沙星)中加入ICE抑制剂可进一步改善角膜疾病的结果。
重要的是,申请人已经证实ICE抑制不仅对标准ATCC实验菌株(19660)有效,而且对临床分离物(KEI-1025)也有效。此外,发现ICE抑制可有效抗来源于亲代19660株的环丙沙星抗性株。在被环丙沙星抗性绿脓假单胞菌菌株感染后,ICE抑制剂治疗的角膜的临床得分显著降低。
各种研究(Chaudhry等人,1999;Garg等人,1999;Kowalski等人,2001;Kunimoto等人,1999)已经显示出体外抗细菌剂抗性和角膜炎患者应答抗细菌剂临床失败之间的关联。Garg等人(1999)报道了在141例经证实的假单胞菌角膜炎培养物中,有22例是由对环丙沙星产生抗性的分离物所引起的(平均MIC 43mg/ml)。在最初用环丙沙星治疗的(22例中的)19例中,3天强化治疗后,15例(76.7%)恶化或表现出没有临床改善且需要改进抗细菌治疗、角膜移植或去脏术。假单胞菌抗生素抗性发生率的增加和导致不利结果的对抗细菌治疗应答的失败为研究新的治疗策略提供了有力的原因。ICE抑制剂可以是抗生素抗性假单胞菌角膜炎病例的新的治疗策略。因此,本发明提供了一种控制细菌生长的方法,特别是在由抗生素抗性菌株引起的微生物角膜炎病例中。
由任何微生物或病原性物质,如US 2004/0229802(见,特别是,段落0028-0039)中所公开那些导致的感染可根据本发明进行治疗。正如所理解的那样,这类病原性物质可引起刺激、炎症、发红、疼痛、组织损害、和其它副作用和症状。因此,本发明的方法可用于改善、治疗、或预防受治疗者的感染,或其症状(包括细菌感染、病毒感染、寄生虫感染、或真菌感染),包括给予受治疗者抑制ICE的化合物。在优选实施方案中,该方法用于改善、治疗或预防眼睛感染。在优选实施方案中,该方法用于改善、治疗、或预防角膜炎(包括浸润性角膜炎)或角膜溃疡。可从本发明的治疗受益的其它眼睛疾病包括,但不限于,US 2004/0229802(见,特别是,段落0025)中描述的那些。还包括与接触镜片使用有关的感染(例如,与接触镜片有关的红眼(CLARE)、接触镜片诱导的外周溃疡(CLPU))。
在另一实施方案中,本发明提供了一种减少受治疗者细菌生长的方法,包括给予受治疗者抑制ICE的化合物。在另一实施方案中,本发明提供了一种共同给予ICE抑制剂和抗微生物剂,由此减少受治疗者细菌生长的方法。
在另一实施方案中,本发明提供了一种改善、治疗或预防受治疗者眼睛的损伤、变态反应、化学刺激、或烧伤的方法,包括给予受治疗者抑制ICE的化合物。在优选实施方案中,本发明提供了促进眼睛损伤愈合并提高视觉清晰度的方法。在优选实施方案中,眼睛损伤是角膜损伤,包括但不限于,擦伤、裂伤、抓伤、手术创伤、意外或偶然创伤、和挫伤。在另一实施方案中,本发明提供了一种改善、治疗或预防干眼症(干性角膜结膜炎)、斯耶格伦氏综合症、眼睛衰老的方法,包括给予受治疗者抑制ICE的化合物。另一方面,本发明可用于改善、治疗或预防感染或与眼睛手术有关的感染或炎症或疼痛的副作用。
本发明特别用于治疗眼睛表层组织的炎症或变红。与炎症有关的眼睛疾病包括,例如,结膜炎(细菌性结膜炎、真菌性结膜炎、或病毒性结膜炎)、眼色素层炎、角膜后沉着物、斑性水肿、眼内晶状体移植后的炎性反应、和由眼睛手术或眼睛损伤引起的创伤。在另一实施方案中,本发明提供改善、治疗或预防这些疾病的方法。
因此,本发明提供了改善、治疗或预防眼睛的刺激、炎症、发红、疼痛、组织损害、和其它不利症状的方法。
该化合物可用于治疗受治疗者如动物,优选哺乳动物,且更优选人的疾病和病症,包括感染疾病状态。本发明的方法可用于兽医环境包括动物园、实验室、和农场动物。因此,受治疗者包括动物,如灵长类动物、啮齿动物、和鸟(包括但不限于,豚鼠、仓鼠、沙土鼠、大鼠、小鼠、兔子、狗、猫、马、猪、绵羊、牛、山羊、恒河猴、猴、绢毛猴(tamarinds)、猿、狒狒、大猩猩、黑猩猩、猩猩、长臂猿、鸡、火鸡、鸭、鹅、鹿和鸵鸟)。
抑制ICE的任何化合物均可用于本发明的方法和组合物中。这类化合物包括选择性抑制ICE的那些化合物和抑制天冬氨酸特异性半胱氨酸蛋白酶或ICE/CED-3家族中一种或多种酶的那些化合物。这种ICE抑制剂包括但不限于,WO 04/058718、WO 04/002961、WO 03/088917、WO 03/068242、WO 03/042169、WO 98/16505、WO 93/09135、WO 00/55114、WO 00/55127、WO 00/61542、WO 01/05772、WO 01/10383、WO 01/16093、WO 01/42216、WO 01/72707、WO 01/90070、WO 01/94351、WO 02/094263、WO 02/42278、WO 03/106460、WO 03/103677、WO 03/104231、US6,184,210、US 6,184,244、US 6,187,771、US 6,197,750、US6,242,422、2001年4月在美国加利福尼亚San Diego召开的AmericanChemical Society(ACS)会议、WO 02/22611、US 2002/0058630、WO02/085899、WO 95/35308、US 5,716,929、WO 97/22619、US 6,204,261,WO 99/47545和WO 01/90063(这些,如本文提出的,全文引入本文作为参考)中描述的化合物。用于本发明的优选化合物在WO 04/058718、WO 04/002961、WO 95/35308、US 5,716,929、WO 97/22619、US6,204,261、WO 99/47545和WO 01/90063中描述。
还包括结构的所有异构体(例如,对映异构、非对映异构、和几何异构(或构象异构))形式;例如,各不对称中心的R和S构型、(Z)和(E)双键异构体、及(Z)和(E)构象异构体。因此,本发明化合物的单一立体化学异构体以及对映异构、非对映异构、和几何(或构象)混合物落在本发明的范围之内。除非另有说明,本发明化合物的所有互变异构形式均落在本发明的范围之内。此外,除非另有说明,本文所述结构还包括区别仅在于存在一个或多个同位素富集原子的化合物。例如,具有所列结构,区别在于氢被氘或氚取代,或碳被13C-或14C-碳取代的化合物落在本发明的范围之内。
本发明所用化合物还可通过附加适当的官能团而被修饰,从而提高选择性生物学性质。这种修饰是本领域熟知的且包括增加向规定生物学系统(例如,血液、淋巴系统、或中枢神经系统)中的生物学渗透、增加口服可利用率、增加溶解度以注射给药、改变代谢和/或改变分泌速率的那些。
本发明更优选的化合物包括:
及其各自的立体异构体,包括:
及其各自的立体异构体,包括:
及其各自的立体异构体,包括:
及其各自的立体异构体,包括:
本发明的化合物可抑制ICE和/或降低IL-1,特别是IL-1β和IL-18水平。可测定这些化合物例如抑制IL-1β和/或IL-18产生,调节IL-1β和/或IL-18水平,和/或影响IL-1β和/或IL-18活性的能力。各种活性的测定法是本领域熟知的,包括下面描述的实施例中的那些。因此,这些化合物能够靶向并抑制本文提出的ICE和/或IL-1β介导的疾病中的事件。
本发明还提供根据本文所述和本领域已知的方法,测定化合物(ICE抑制剂)抗-感染活性的方法。
因此本发明的药物组合物和方法可用于控制体外或体内IL-1β水平和/或活性。因此本发明的组合物和方法可用于控制体内IL-1β水平并治疗或降低特定情况,包括本文提出的疾病、病症或效应的发展、严重程度或效应。
根据另一实施方案,本发明提供一种组合物,它包含上述本发明的化合物(ICE抑制剂)或其药学可接受的衍生物(例如,盐)以及药学可接受的载体。
根据另一实施方案,本发明的组合物可进一步包含其它治疗剂。这种药剂包括,但不限于,溶解血栓的药剂如组织纤溶酶原激活剂和链激酶、抗-炎剂、基质金属蛋白酶抑制剂、脂氧合酶抑制剂、细胞因子拮抗剂、免疫抑制剂、抗-癌剂、抗-病毒剂、细胞因子、生长因子、免疫调节剂(例如,溴匹利明、抗-人α干扰素抗体、IL-2、GM-CSF、甲硫氨酸脑啡肽、干扰素α、二乙基二硫代氨基甲酸盐、肿瘤坏死因子、纳曲酮和rEPO)、前列腺素、或抗-血管过度增殖化合物。其它药剂包括,但不限于,下列一种或多种:另外的ICE抑制剂、NSAID(见,例如,WO 01/08689)、抗微生物剂、抗细菌剂、抗-炎剂、和其它药剂,条件是它们不会与本发明的目的相矛盾(包括,但不限于,US2004/0191332,特别是段落0042-0051和WO 01/08689中描述的药剂)。
在仅含本发明化合物作为活性组分的药物组合物中,给予这些组合物的方法可另外包括给予受治疗者另外的药物,如本文所述那些的步骤。当使用第二种药剂时,可以以分开的剂量形式或作为混合了本发明化合物或组合物的单一剂量形式的一部分该给予第二种药剂。
术语“药学可接受的载体”是指可连同本发明化合物给予患者,且不会破坏其药理学活性的无毒载体。
可用于这些组合物中的药学可接受的载体包括,但不限于,离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白如人血清白蛋白、缓冲物质如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢二钾、氯化钠、锌盐、胶态二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段共聚物、聚乙二醇和羊毛脂。
存在于上述组合物中的化合物的用量应足以引起疾病严重程度、或ICE抑制、IL-1和/或IL-18水平、或IL-1和/或IL-18活性的可检测的降低。
如果将本发明化合物药学可接受的盐用于这些组合物中,则那些盐优选来源于无机或有机酸和碱。酸式盐包括下列:乙酸盐、己二酸盐、藻酸盐、天门冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、延胡索酸盐、葡糖庚酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、草酸盐、扑酸盐、果胶酯酸盐、过硫酸盐、3-苯基-丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐和十一烷酸盐。碱式盐包括铵盐、碱金属盐,如钠和钾盐、碱土金属盐,如钙和镁盐、有机碱盐,如二环己胺盐、N-甲基-D-葡糖胺和与氨基酸的盐,如精氨酸、赖氨酸的盐等。
也可以使用下列试剂将碱性含氮基团季铵化,如低级烷基卤,如甲基、乙基、丙基、和丁基氯、溴、和碘;二烷基硫酸盐,如二甲基、二乙基、二丁基和二戊基硫酸盐;长链卤化物如癸基、十二烷基、十四烷基和硬脂酰氯、溴和碘;芳烷基卤,如苄基和苯乙基溴和其它。由此获得水或油-溶性或分散性产物。
根据优选实施方案,将本发明的组合物配制成药用给予受治疗者的形式,例如,哺乳动物,优选人。
本发明这类药物组合物可口服、非肠道、通过吸入喷雾剂、局部、直肠、鼻、口腔、阴道或经由植入的贮器给药。本文所用术语“非肠道”包括皮下、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、肝内、损害内和颅内注射和输注技术。优选,将组合物配制成用于眼睛给药的形式。
本发明组合物的无菌可注射形式可以是含水或含油混悬液。这些混悬液可根据本领域已知的技术,使用适宜的分散或湿润剂和悬浮剂配制。该无菌可注射制剂还可以是溶于无毒的非肠道可接受的稀释剂或溶剂中的无菌可注射溶液或混悬液,例如,溶于1,3-丁二醇中的溶液。所用可接受的载体和溶剂是水、林格氏溶液和等渗氯化钠溶液。此外,无菌的不挥发油也常用作溶剂或悬浮介质。就该目的而言,可使用任何温和的不挥发油,包括合成的单-或二-甘油酯。脂肪酸,如油酸及其甘油酯衍生物也可用于可注射制剂的制备,因为它们是天然的药学可接受的油,如橄榄油和蓖麻油,特别是它们的聚氧化乙基化形式。这些油溶液或混悬液还可含有长链醇稀释剂或分散剂,如羧甲基纤维素或类似的分散剂,它们通常用于配制药学可接受的剂量形式,包括乳液和混悬液。其它常用的表面活性剂,如吐温、司盘和其它乳化剂或生物可利用率增强剂,它们通常用于制造药学可接受的固体、液体、或其它剂量形式,也可用于配制的目的。
如果使用固体载体,可将该制品压片、以粉末或颗粒形式放在硬明胶胶囊中、或是锭剂或糖锭的形式。固体载体的用量将在约25mg-400mg变化。当使用液体载体时,该制品可以是糖浆剂、乳液、软明胶胶囊、无菌可注射液体如安瓿或非水性液体混悬液的形式。当组合物为胶囊形式时,任何常规的胶囊化都是适宜的,例如,在硬明胶胶囊壳中使用上述载体。
糖浆制剂可包括化合物溶于液体载体(例如含调味剂或着色剂的乙醇、甘油或水)中的混悬液或溶液。气溶胶制品可包括化合物溶于液体载体(如水、乙醇或甘油)中的溶液或混悬液;而在干粉气溶胶中,该制品可包括,如,湿润剂。
本发明的制剂包括活性成分及其一种或多种可接受的载体和任选的任何其它治疗成分。从与制剂其它成分相容的意义上说,载体应是“可接受的”且对其受体无害。
本发明的药物组合物可以任何口服可接受的剂量形式口服给药,包括,但不限于,胶囊剂、片剂和含水混悬液或溶液。就口服使用的片剂而言,通常使用的载体包括乳糖和玉米淀粉。通常还加入润滑剂,如硬脂酸镁。以胶囊形式口服给药时,有效的稀释剂包括乳糖和干玉米淀粉。当含水混悬液需要口服使用时,将活性成分与乳化和悬浮剂混合。如需要,还可加入特定甜味剂、调味剂或着色剂。
或者,本发明的药物组合物可以直肠给药的栓剂形式给予。这些可通过将药剂与适宜的无-刺激性赋形剂混合而制备,所述赋形剂在室温下为固体,而在直肠温度下为液体,且因此在直肠中融化而释放出药物。这类物质包括椰子油、蜂蜡和聚乙二醇。
本发明的药物组合物还可局部给药,特别是当治疗的靶包括很容易通过局部应用而进入的区域或器官时,包括眼睛、皮肤或肠道下部的疾病。适宜的局部制剂很容易相对于这些区域或器官分别制备。
肠道下部的局部应用可以直肠栓剂(见上面)或适宜的灌肠剂形式进行。还可使用局部透皮贴剂。
局部应用时,可将药物组合物配制成含有混悬或溶于一种或多种载体中的活性成分的适宜软膏剂。用于局部给予本发明化合物的载体包括,但不限于,矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯化合物、乳化蜡和水。或者,可将该药物组合物配制成适宜的含有混悬或溶于一种或多种药学可接受载体中的活性成分的洗剂或霜剂。适宜的载体包括,但不限于,矿物油、脱水山梨糖醇一硬脂酸酯、聚山梨醇酯60、十六烷基酯蜡、鲸蜡硬脂醇、2-辛基十二烷醇、苄醇和水。
在眼用组合物中,载体应是眼睛可接受的,即应当是在讨论的浓度或用量下,与眼睛组织相容的物质。当与眼睛组织接触时,这类物质不会引起显著或不适当的有害作用。这类载体的例子是本领域技术人员已知的(见例如,WO01/08689和US2004/0229802)。优选含水载体,特别是含至少50重量%水的那些。
在眼用组合物中,载体可包括一种或多种药学或眼睛可接受的成分,如渗透压(或等渗)调节剂、缓冲剂、粘度剂(例如,增稠剂)、润滑剂、表面活性剂、防腐剂、乳化剂、湿润剂、增稠剂、触变剂、缓和剂和通常用于眼用制剂中的其它成分。这类载体和眼睛可接受成分的例子是本领域技术人员已知的(见,例如,WO01/08689、US2004/0198763、US2004/0191332、US2004/0191332和US2004/0229802,其在本文提出,全文引入作为参考)。
优选,眼用组合物的pH为目标受治疗者的生理学范围(例如,约3、4或5-约7.5、8.5或9,优选约7、约7.5或约8)。
本发明的眼用组合物可以是适于给予眼睛的任何形式,如溶液、混悬液、软膏、凝胶、和固体(见,例如,WO01/08689)。还包括固体插入物和人造眼泪组合物。
眼用时,可将药物组合物配制成溶于等渗、pH调节的无菌盐水中的微粉化混悬液或,优选,溶于等渗、pH调节的无菌盐水中的溶液,其含有或不含防腐剂如苯扎氯铵(benzylalkonium chloride)。或者,眼用时,可将药物组合物配制成软膏剂,如在凡士林中配制。在其中一个实施方案中,按照本文所述配制该组合物。其它眼用制品可在,例如,美国专利US6,645,994和/或美国专利US6,630,473中找到。
本发明的药物组合物还可通过鼻气溶胶或吸入给药。这种组合物是按照药物制剂领域熟知的技术制备的且可制备成溶于盐水中的溶液,其中使用苄醇或其它适宜的防腐剂,提高生物可利用率的吸收促进剂、氟碳和/或本领域已知的其它常规溶解或分散剂。
本发明的组合物还可包括螯合或多价螯合组分或稳定剂(如WO01/08689和US2004/0229802中描述的那些)。
本发明的组合物可按照常规技术制备。本发明其中一个实施方案提供一种制备滴眼组合物的方法,包括将ICE抑制剂和载体(优选无菌纯化水)混合且任选包括混合本文所述的另外的药物。眼用软膏剂可通过将ICE抑制剂和基质混合而制备(见,例如,US2004/0198763)。
本领域技术人员应认识到药学可接受载体或稀释剂的形式和性质由与其混合的活性成分用量、给药途径和其它熟知的变量决定。
眼用和其它制剂的制备和给药的描述可在Remington:TheScience and Practice of Pharmacy(以前的Remington′sPharmaceutical Sciences)中找到。
上述化合物和组合物还用于和特定感染疾病有关的治疗应用。
本发明的化合物可抑制释放IL-1β和/或IL-18,并由此可用于抑制或阻断本文提出的特定疾病的若干病理生理学作用。
本发明还涉及一种通过(1)抑制IL-1β和/或IL-18从细胞释放和/或(2)防止哺乳动物(包括人)中过高组织水平的IL-1β和/或IL-18的不利、有毒或致命作用而治疗特定疾病的治疗方法。该方法包括给予哺乳动物有效ICE抑制量的一种或多种ICE/CED-3抑制剂。该方法还可用于特定疾病的预防性治疗或预防,包括细菌感染、病毒感染、真菌感染和寄生虫感染。本发明提供一种对有此需要的哺乳动物,包括人给予有效量的(即,治疗有效量)的这类化合物而治疗这些疾病的方法。
这些化合物,通过抑制ICE和阻断IL-1β和/或IL-18释放或降低IL-1β和/或IL-18水平和活性,以及在这些情况中过量水平的IL-1β和/或IL-18的病理生理学作用,直接促进特定疾病的抑制或消除,并促进正常功能的恢复。同时,这些作用涉及它们在治疗感染性疾病中的新用途。
ICE抑制可通过本领域已知和本文更全面描述的方法测量。
这些化合物可用于抑制单核细胞、巨噬细胞、神经元细胞、内皮细胞、表皮细胞、间质细胞(例如,成纤维细胞、骨骼肌细胞、平滑肌细胞、心肌细胞)和许多其它类型细胞释放IL-1β和/或IL-18。
术语“情况”或“状态”是指在受治疗者中产生有害生物学结果的任何疾病、病症或作用。
患者的血液或细胞或细胞培养物中(即,细胞或细胞培养基内)的IL-1β和/或IL-18蛋白水平可通过下列方法测定,例如,与IL-1β和/或IL-18或已知由于活性IL-1β和/或IL-18的存在而产生的其它蛋白免疫特异性结合的测定法。这种方法是本领域已知的。例如,可使用的免疫测定法包括,但不限于,竞争性和非-竞争性测定系统、蛋白质印迹、放射性免疫测定法、ELISA(酶联免疫吸附测定法)、“三明治”免疫测定法、免疫沉淀测定法、沉淀反应、凝胶扩散沉淀反应、免疫扩散测定法、凝集测定法、补体-固定测定法、免疫放射测定法、荧光免疫测定法、蛋白A免疫测定法和使用标记抗体进行的FACS分析。这类测定法是本领域熟知的(见,例如,Ausubel等人eds,1994,Current Protocols in Molecular Biology,Vol.1,John Wiley &Sons,Inc.,New York,其全文引入本文作为参考)。
竞争性结合测定法还可用于测定IL-1β和/或IL-18的水平。竞争性结合测定法的其中一个例子是放射免疫测定法,包括在有增量未标记IL-1β存在的条件下,用抗-IL-1β抗体培养来源于表达IL-1β的细胞的标记蛋白(例如3H或125I),并检测与标记的IL-1β结合的抗-IL-1β抗体。目标抗体对特定抗原的亲和性及结合分离率(bindingoff-rates)可根据Scatchard绘图分析由数据测定。与第二种抗体的竞争还可使用放射免疫测定法测定。在这种情况下,在有增量未标记的第二种抗体存在的条件下,将抗原与和标记化合物(例如,3H或125I)接合的目标抗体一起培养。
IL-1β和/或IL-18水平还可通过活性测定,例如,IL-1β水平可通过能够检测细胞因子(如IL-1或生长因子)的生物活性水平的细胞系测定。根据其中一个实施方案,生物学样品中生物活性的IL-1β的水平是通过用异丙基-b-D-硫代半乳吡喃糖苷培养基因工程改造的细胞系而检测的。将细胞系与所检测样品进行培养并通过测定表示所检测样品中生物活性细胞因子或生长因子的蓝色强度而监测细胞系中的细胞死亡。[还参见,例如,X.-S.Liu,Burns 20(1),pp.40-44(1994),用于TNF监测]
在单一疗法中使用约0.01-约100mg/kg体重/天、优选约0.5-约75mg/kg体重/天且最优选约1-约50mg/kg体重/天的活性成分化合物的剂量水平。在局部用(例如,滴眼)制剂中,约300nM-3mM,优选约3μM-约300μM的ICE抑制剂浓度是有效的。这种局部眼用制剂将根据需要给药,优选速率为约1-约10滴/眼和约1-约10次/天。在本发明其它眼用制剂中,ICE抑制剂以至少约0.001%(w/v或w/w)、至少约0.03%(w/v或w/w)、至少约0.15%(w/v或w/w)的量和不超过约10%(w/v或w/w)、不超过约3%(w/v或w/w)、不超过约1%(w/v或w/w)或不超过约0.5%(w/v或w/w)的量存在。如果存在,防腐剂的量为至少约0.0001wt%、约0.1wt%、约0.2wt%-约0.5wt%、约1wt%、或约2.5wt%。
通常,可每天约1-5次给药或者连续输注给予本发明的药物组合物。这种给药可用作慢性或急性治疗。与载体物质混合,以产生单一剂量形式的活性成分的用量将根据所治疗的宿主和特定的给药方式而变化。典型的制剂含有约5%-约95%活性化合物(w/w)。优选,这类制品可含有约20%-约80%活性化合物。
当本发明组合物含本发明化合物与一种或多种另外的治疗剂的组合时,化合物和另外的药物应以占单一治疗方案通常给药剂量的约10%-约80%的剂量水平存在。
患者的情况改善后,如果需要,可给予维持剂量的本发明化合物、组合物或组合。随后,可根据症状降低给药剂量或频率,或两者均降低,达到保持情况改善的水平。当症状已经减轻至所需水平时,治疗应停止。然而,患者可以在任何复发或疾病症状后,要求长期间歇治疗。
还应理解,任何特定患者的具体剂量和治疗方案将取决于多种因素,包括所用具体化合物的活性、年龄、体重、一般健康状况、性别、饮食、给药时间、分泌速率、药物组合、及治疗医师的判断和所治疗特定疾病的严重程度。活性成分的用量还取决于组合物中特定的化合物以及,如果存在,其它治疗剂。
因此,治疗或预防受治疗者中本发明所述疾病的方法包括给予受治疗者本文所述任何化合物、药物组合物、或组合的步骤。
在优选实施方案中,本发明提供一种治疗患有上述其中一种疾病的哺乳动物(优选,人)的方法,包括给予所述哺乳动物上述药学可接受的组合物的步骤。在该实施方案中,如果还给予患者其它治疗剂,它可与本发明化合物一起以单一剂量形式递送,或,作为分开的剂量形式递送。当以分开的剂量形式给药时,可在给予含本发明化合物的药学可接受的组合物之前,之时、或之后给予其它治疗剂。
本发明还提供了根据本文所述和本领域已知的方法测定化合物(ICE抑制剂)抗-感染活性的方法。
用于鉴别治疗本发明所述疾病的化合物或组合物的方法包括筛选许多化合物或组合物减轻特定疾病的效应和/或改善患有本发明特定疾病患者情况的能力的方法。根据本发明其中一个实施方案,高通量筛选可通过下列方法进行:在微量滴定平板的多个孔中培养细胞,向各孔中加入不同的化合物或组合物并将各孔培养物中的ICE抑制作用和/或IL-1β和/或IL-18水平和/或活性与对照孔细胞培养物中的水平或活性进行比较。用于本发明比较步骤的对照组包括没有用化合物或组合物处理的细胞或受治疗者和使用已知对ICE抑制或活性没有作用的化合物或组合物处理的细胞或受治疗者。
根据本发明其中一个实施方案,高通量筛选是自动化的,步骤包括将细胞加入到平板中直到数据采集,且加入化合物或组合物后的分析由机器进行。用于本发明比较步骤的仪器,例如,可检测标记物质(例如,放射性标记的、荧光或彩色标记的物质)或本身是可检测的物质的仪器从商业得到和/或本领域已知。因此,可迅速且有效地筛选用于治疗本文公开的特定疾病的本发明的化合物和组合物。
其中一个实施方案提供了一种鉴别减轻、治疗、或预防感染疾病(或这里公开的其它疾病或病症)的化合物的方法,包括使感染的细胞种群或细胞培养物与抑制ICE的化合物接触,并将细胞种群或细胞培养物中的感染量与没有用ICE抑制剂处理的细胞种群或细胞培养物中的感染量进行比较。
另一实施方案提供了一种鉴别减轻、治疗、或预防受治疗者中感染疾病状态的化合物的方法,包括给予任何下列文献中所述的ICE抑制剂或含该化合物的药物组合物,并比较用化合物治疗之前和之后,受治疗者的感染疾病状态:WO 04/058718、WO 04/002961、WO03/088917、WO 03/068242、WO 03/042169、WO 98/16505、WO 93/09135、WO 00/55114、WO 00/55127、WO 00/61542、WO 01/05772、WO 01/10383、WO 01/16093、WO 01/42216、WO 01/72707、WO 01/90070、WO 01/94351、WO 02/094263、WO 02/42278、WO 03/106460、WO 03/103677、WO03/104231、US 6,184,210、US 6,184,244、US 6,187,771、US6,197,750、US 6,242,422、2001年4月在美国加利福尼亚San Diego召开的American Chemical Society(ACS)会议、WO 02/22611、US2002/0058630、WO 02/085899、WO 95/35308、US 5,716,929、WO97/22619、US 6,204,261、WO 99/47545和WO 01/90063。
本发明另一方面包括一种患者在本发明治疗中使用的包装试剂盒,包括:各药物组分的单一或多个药物制剂;在贮存过程中和给药之前盛装药物制剂的容器;和以有效进行本发明方法的方式进行药物给药的说明。通常,这种试剂盒包含,例如,各ICE抑制剂和任选的另外的药物以及药学可接受载体的组合物(和一种或多种药物制剂)以及同时或顺序给药的书面说明。该试剂盒还包含固体形式的ICE抑制剂和药学可接受的载体以及用于制备药物组合物的书面说明。
在另一实施方案中,提供了一种包装试剂盒,它含有用于自我给药的一个或多个剂量形式;用于在贮存过程中和使用之前盛装剂量形式的容器,优选密封的;和对患者进行药物给药的说明书。该说明书通常是包装插入物、标签、和/或试剂盒其它组件上的书面说明,且一种或多种剂量形式是如本文所描述的。各剂量形式可单独盛装在金属箔-塑料层压品片中,其中各剂量形式与独立室或泡中的其它剂量形式分开,或可将剂量形式盛装在单一容器中,如塑料瓶中。本发明试剂盒通常还包括用于包装各试剂盒组件的工具,即剂量形式、容器、和使用书面说明的工具。这种包装工具可采用纸板或纸盒、塑料或箔袋等的形式。
本文公开的所有申请、专利和参考文献均引入作为参考。
为了更全面了解本发明,给出下列制备和试验实施例。这些实施例仅用于举例说明的目的,而不解释为以任何方式限制本发明的范围。
实施例
实施例1
动物感染
在这些实验中使用8周大的雌性B6小鼠(The Jackson Laboratory,Bar Harbor,ME)。在立体显微镜下,使用无菌255/8号针,用三个平行的1mm切口划破各麻醉小鼠的左角膜。用1.0×106CFU/μl绿脓假单胞菌(如前所述,5μl剂量,ATCC菌株19660或临床分离物-1025或环丙沙星抗性19660菌株(Kwon和Hazlett,1997))局部攻击划破的角膜。在感染后(p.i.)第1天和下述时间,肉眼检查眼睛以确保所有小鼠均类似被感染并监测疾病的病程。所有动物均被人道处理且在研究中,有关动物的使用和处理完全遵从Association for ResearchinVision and Ophthalmology决议。
实施例2
细菌菌株
将绿脓假单胞菌菌株19660用作标准实验室菌株并在B6小鼠模型中产生可再现的角膜病变(Kernacki等人,2000;Rudner等人,2000)。1999年,在Kresge Eye Institute,Detroit,MI,从人微生物角膜炎病例中分离出了绿脓假单胞菌菌株1025(KEI-1025)。实验室-衍生的环丙沙星-抗性突变体是通过在含环丙沙星的Luria-Bertani(LB)肉汤中连续传代野生型绿脓假单胞菌菌株19660从而获得环丙沙星抗性而研制出来的(Sanchez等人,2002)。与亲代菌株相比,环丙沙星-抗性绿脓假单胞菌菌株显示出体外杀死细菌所需的环丙沙星最小抑制浓度(MIC)增加了100-倍(0.25mg/ml对25mg/ml)。在该突变体的体外产生过程中,环丙沙星-抗性(绿脓假单胞菌19660)突变体的毒性与亲代菌株相比降低,其并不罕见且先前已经报道过(Bjorkman等人,1998)。
实施例3
ICE抑制剂的制剂
与其它非-ICE天冬氨酸特异性半胱氨酸蛋白酶相比,这些实验中所用的ICE抑制剂显示出有效的ICE抑制(Ki=0.8nM)和>100倍的选择性。研究了4种含或不含ICE抑制剂(300μM)载体(PBS)的盲编码制剂的结膜下和局部给药。发现所有制剂对另外未处理的小鼠眼睛均无毒,且没有直接(体外)杀死细菌的能力。
实施例4
处理方案
在p.i.第18小时,给B6小鼠(n=5/组)结膜下注射5□□1600□M浓度的ICE抑制剂或安慰剂,接着在p.i.第18小时开始,局部应用D(ICE抑制剂)或C(安慰剂)+/-环丙沙星(Ciloxan;Alcon,Ft.Worth,TX),3x/天共7天。在p.i.第18小时选择开始ICE抑制剂治疗,从而进行实验检测,以提供更多临床相关的数据。此外,到该时间点止,预期患者将注意到眼睛的症状如模糊、不适和疼痛且会小心摸索。
实施例5
临床检验
将小鼠(n=5/组)用颜色编码,并以遮蔽方式由两名独立的观察者,在p.i.第1、3、5和7天时检查,评价绿脓假单胞菌感染后疾病的严重程度。评价眼病并使用下列已确立的等级(Hazlett等人,1987)表示临床得分:0,澄明或稍混浊,部分覆盖瞳孔;+1,稍混浊,完全覆盖前面的部分;+2,密集的混浊,部分或完全覆盖瞳孔;+3,密集的混浊,覆盖前面的部分;和+4,角膜穿孔。
实施例6
病理组织学
进行病理组织学检查时,在p.i.第7天,摘除ICE抑制剂或安慰剂+/-环丙沙星处理的小鼠眼睛(n=3/组)。将眼睛浸泡在PBS中,冲洗并放在4℃下、含1∶1∶1比例的1%四氧化锇、2.5%戊二醛、和0.2MSorenson′s磷酸盐缓冲液(pH 7.4)的固定液中3小时。将眼睛转移到新鲜的固定液中,1.5小时后,在梯度乙醇中脱水,包埋在Epon-araldite中,切片,用改性的Richardson′s染料染色并如以前所述照相(Hazlett等人,2000)。
实施例7
髓过氧化物酶(MPO)活性的测量
如以前所述,测定样品的MPO活性(Williams等人,1982)。在p.i.第7天采集ICE抑制剂或安慰剂+/-环丙沙星处理的小鼠角膜(n=5/组)并在1ml的溴化十六烷基三甲铵(HTAB)缓冲液(0.5%HTAB,溶于50mM磷酸盐缓冲液,pH 6.0)中匀化。使样品经过3次冻-融循环,然后14,000rpm离心20分钟。将上清液与共3ml体积、含1∶30的0.167mg/ml O-联茴香胺盐酸盐和0.0005%过氧化氢的50mM磷酸盐缓冲液(pH 6.0)混合。连续监测460nm处吸光度的变化达5分钟。结果以MPO的单位/角膜表示。一个单位的MPO活性相当于约2.0×105PMN细胞(Williams等人,1982)。
实施例8
角膜中活细菌的量化
在p.i.第7天,采集ICE抑制剂或安慰剂+/-环丙沙星处理的小鼠角膜(n=5/组)并测定活细菌数。为此,将各角膜在无菌PBS中匀化并一式三份将连续稀释的等分试样(100μl)接种在假单胞菌分离琼脂(Difco,Detroit,MI)平板中。37℃培养平板24小时。结果以CFu的log10数/角膜+SEM表示。
实施例9
角膜匀浆中细胞因子蛋白的量化
按照制造商的说明,使用ELISA试剂盒(R&D Systems,Minneapolis,MN)检测ICE抑制剂或安慰剂+/-环丙沙星处理的小鼠中IL-1β和MIP-2的蛋白水平。在p.i.第7天除去角膜(n=5/组)并立即在-70℃贮存。分析之前,用玻璃Kontes研棒(Fisher,Itasca,IL)在0.1%吐温20-PBS中匀化各角膜,4℃下,5000×g离心10分钟,上清液用于量化IL-1β和MIP-2蛋白。结果以pg/ml报告。
实施例10
统计学分析
组内临床得分随时间的变化是通过排列、由方差的Friedman双向分析检测的。ICE抑制剂和安慰剂处理的B6小鼠之间,在各实验时间点的临床得分差异是通过Mann-Whitney U试验检测的。不成对的,双尾Student’s t-试验用于测定处理组和对照组之间的MPO测定、细菌计数和ELISA分析数据的统计学显著性差异。P□0.05的平均差异被认为是显著的。实验重复至少2次以确保再现性,并给出单一实验的代表性数据。
实施例11
结果
与载体-处理的小鼠相比,ICE抑制剂-处理的小鼠在p.i.第3(P=0.012)、5(P=0.007)和7(P=0.007)天表现出疾病严重程度明显降低。使用ICE抑制剂和环丙沙星联合治疗还导致与载体和环丙沙星-处理组相比,p.i.第5(P=0.050)和7(P=0.047)天,临床得分明显降低。除了ICE抑制剂+环丙沙星治疗组外,还观察到组内临床得分随时间变化的显著性差异(载体,P=0.0001;载体+环丙沙星,P=0.009;ICE抑制剂,P=0.0014;ICE抑制剂+环丙沙星,P=0.77)。
在ICE抑制剂处理的小鼠中,与载体-处理的小鼠相比,在p.i.第3(P=0.007)、5(P=0.015)和7(P=0.007)天发现疾病严重程度明显降低(绿脓假单胞菌KEI-1025)。与在感染绿脓假单胞菌菌株19660的角膜中用ICE抑制剂和环丙沙星处理类似,与载体加环丙沙星处理的角膜相比,在B+D和环丙沙星处理的角膜中,p.i.第3(P=0.007)、5(P=0.015)和7(P=0.031)天,该组(感染KEI-1025)临床得分也明显降低。该组临床得分随时间的变化而明显不同(载体,P=0.0001;载体+环丙沙星,P=0.04;ICE抑制剂,P=0.0002;ICE抑制剂+环丙沙星,P=0.04)。
使用ICE抑制剂治疗感染绿脓假单胞菌(19660)环丙沙星抗性菌株的角膜时,与载体处理的小鼠相比,显示p.i.第3(P=0.03)、5(P=0.03)和7(P=0.007)天,临床得分明显降低。同样,在ICE抑制剂和环丙沙星处理的组中,观察到与载体和环丙沙星的处理组相比,p.i.第3(P=0.03)、5(P=0.03)和7(P=0.007)天,临床得分明显降低。ICE抑制剂和环丙沙星处理的小鼠表现出与ICE抑制剂类似的临床得分(相对于载体处理的小鼠),证实了该菌株对环丙沙星的体内抗性。在载体(P=0.01)和ICE抑制剂(P=0.002)处理组中,临床得分随时间变化而明显不同。在载体+环丙沙星,或ICE抑制剂+环丙沙星处理组中,没有观察到临床得分随时间变化的差异。
p.i.第7天,在ICE抑制剂(与载体相比)处理组中进行的裂隙灯显微镜检查证实了临床得分。在ICE抑制剂处理的角膜中,观察到细胞浸润明显更少,其主要位于瞳孔上的中心角膜处。在下方角膜区见到的混浊是由于浸润细胞重力沉降到前房中。相反,所有用载体处理的小鼠均显示角膜穿孔。在ICE抑制剂和环丙沙星处理的角膜中进行的裂隙灯检查显示出与载体和环丙沙星处理的角膜相比,较轻微的角膜混浊,其表明在角膜及前房中,细胞浸润更严重。
ICE抑制剂处理后的眼睛的病理组织学检查显示角膜基质中的浸润细胞显著降低,具有最小前房炎性细胞反应。相反,载体处理的B6小鼠显示角膜中的细胞浸润较为严重,具有角膜上皮完全剥脱、中心基质降解、严重水肿和严重前房炎性细胞反应。用ICE抑制剂和环丙沙星处理的角膜显示与典型的用载体和环丙沙星处理的眼睛相比,沿着角膜内皮和前房中仅有很少的炎性细胞,这表明前房中更为严重的炎性细胞浸润和与角膜内皮粘连。
测定髓过氧化物酶(MPO)活性以量化p.i.第7天,ICE抑制剂(与载体相比)处理的小鼠角膜中的PMN浸润。ICE抑制剂处理的小鼠显示与载体处理的小鼠相比,PMN数显著降低(P=0.04)。同样,在ICE抑制剂加环丙沙星与载体加环丙沙星相比处理的小鼠中,p.i.第7天,角膜中的MPO活性显著降低(P=0.0024)。可描述MPO活性单位/角膜(SEM)。
p.i.第7天,测定ICE抑制剂(与载体相比)处理组的角膜中(n=5/组)的活细菌平板数。与安慰剂处理组相比,发现ICE抑制剂处理组角膜中的活细菌数明显降低(P=0.02)。p.i.第7天,在ICE抑制剂和环丙沙星及载体和环丙沙星处理组角膜中的平板计数中未分离出细菌菌落。可描述平均活细菌log10数/角膜(SEM)。
使用ELISA分析,在p.i.第7天,测定ICE抑制剂(与载体相比)处理组中IL-1β和MIP-2的蛋白水平。在ICE抑制剂组检测到与载体处理组相比明显更低的IL-1β(P=0.023)和MIP-2(P=0.012)蛋白水平。环丙沙星处理明显降低了IL-1β和MIP-2水平,推测是由于通过消除感染而使促炎症反应刺激物减少。然而,在ICE抑制剂和环丙沙星处理组中,IL-1β(P=0.036)和MIP-2(P=0.04)的蛋白水平与载体和环丙沙星处理组相比,也进一步且明显降低。
实施例12
ICE抑制
可通过本领域熟知的方法(见,例如,本文引证的文献)测试化合物抑制ICE的能力。
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本文引证的文献引入作为参考。
虽然我们描述了本发明的许多实施方案,但是很明显可对我们的基础实施例进行改变,从而提供其它实施方案,其使用本发明的化合物和方法。因此,应了解本发明的范围是由附加的权利要求而不是已经通过实施例提出的具体实施方案来限定。
Claims (26)
1.一种治疗受治疗者感染的方法,包括给予受治疗者抑制ICE的化合物。
2.根据权利要求1的方法,其中所述感染是细菌、病毒、寄生虫、或真菌感染。
3.根据权利要求1或权利要求2的方法,其中将化合物与选自抗细菌、抗病毒、抗寄生虫、或抗真菌剂的另外的药物共同给药。
4.根据权利要求1的方法,其中所述感染是细菌感染。
5.根据权利要求4的方法,其中另外的药物是抗细菌剂。
6.根据权利要求1-5任何一项的方法,其中所述感染是眼睛感染。
7.根据权利要求6的方法,其中抗细菌、抗病毒、抗寄生虫、或抗真菌剂是眼用药物。
8.一种治疗受治疗者眼睛的损伤、变态反应、化学刺激、或烧伤、干眼症、斯耶格伦氏综合征、眼睛老化的方法,包括给予受治疗者抑制ICE的化合物。
9.根据权利要求8的方法,其中将化合物与另外的药物共同给药。
10.根据权利要求9的方法,其中另外的药物是眼用药物。
11.根据权利要求3或权利要求9的方法,其中将另外的药物与化合物以单一剂量形式给药。
12.根据权利要求3或权利要求9的方法,其中将每种另外的药物与化合物以分开的剂量形式给药。
13.根据权利要求1-12任何一项的方法,其中将化合物配制用于给予眼睛的制剂形式。
14.根据权利要求1-6任何一项的方法,其中化合物是WO04/058718、WO 04/002961、WO 03/088917、WO 03/068242、WO 03/042169、WO 98/16505、WO 93/09135、WO 00/55114、WO 00/55127、WO 00/61542、WO 01/05772、WO 01/10383、WO 01/16093、WO 01/42216、WO 01/72707、WO 01/90070、WO 01/94351、WO 02/094263、WO 02/42278、WO 03/106460、WO 03/103677、WO 03/104231、US 6,184,210、US 6,184,244、US6,187,771、US 6,197,750、US 6,242,422、2001年4月在美国加利福尼亚San Diego召开的American Chemical Society(ACS)会议、WO02/22611、US 2002/0058630、WO 02/085899、WO 95/35308、US 5,716,929、WO 97/22619、US 6,204,261、WO 99/47545、或WO 01/90063的任何一种。
15.根据权利要求14的方法,其中化合物是WO 04/058718、WO04/002961、WO 95/35308、US 5,716,929、WO 97/22619、US 6,204,261、WO 99/47545或WO 01/90063的任何一种。
20.一种改善、治疗或预防受治疗者感染疾病的药物组合物,包含抑制ICE的化合物和药学可接受的载体。
21.根据权利要求20的药物组合物,其中组合物还包含抗细菌、抗病毒、抗寄生虫、抗真菌、或其它眼用药物。
22.根据权利要求20或权利要求21的药物组合物,其中组合物是眼用制剂。
23.一种包含ICE抑制剂和药学可接受载体的眼用组合物。
24.一种包含ICE抑制剂和抗细菌、抗病毒、抗寄生虫、抗真菌或其它眼用药物的药物组合(或治疗组合)。
25.一种包含ICE抑制剂和抗细菌剂的药物组合(或治疗组合)。
26.一种包含ICE抑制剂(和任选的抗细菌、抗病毒、抗寄生虫、抗真菌或其它眼用药物)和使用ICE抑制剂治疗感染的说明书的试剂盒,所述说明书任选包括给予抗细菌、抗病毒、抗寄生虫、抗真菌或其它眼用药物(无论是否包括在试剂盒中)的说明。
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EP2295054A1 (en) * | 2004-05-27 | 2011-03-16 | Vertex Pharmaceuticals Incorporated | Ice inhibitors for the treatment of autoinflammatory diseases |
US8754107B2 (en) | 2006-11-17 | 2014-06-17 | Abbvie Inc. | Aminopyrrolidines as chemokine receptor antagonists |
US9365612B2 (en) | 2010-01-29 | 2016-06-14 | United States Of America As Represented By The Secretary, Department Of Health And Human Services | Caspase inhibitors |
WO2022074134A1 (en) * | 2020-10-07 | 2022-04-14 | Etienne Jacotot | Treatments of coronavirus infections, cytokine release syndrome, cytokine storm syndrome, or diseases associated with excessive activation of inflammasomes by the use of inhibitors of inflammatory caspases |
FR3114741A1 (fr) * | 2020-10-07 | 2022-04-08 | Etienne Jacotot | Traitements des infections à coronavirus, du syndrome de libération de cytokine, du syndrome de la tempête de cytokines ou des maladies associées à l'activation excessive des inflammasomes par l'utilisation d'inhibiteurs des caspases inflammatoires. |
CN116041419A (zh) * | 2021-10-28 | 2023-05-02 | 苏州裕泰医药科技有限公司 | 羟脯氨酰基-丝氨酸化合物及其制备和应用 |
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DE69939689D1 (de) * | 1998-03-19 | 2008-11-20 | Vertex Pharma | Caspase inhibitoren |
US6201118B1 (en) * | 1998-08-19 | 2001-03-13 | Vertex Pharmaceuticals Inc. | Process for forming an N-acylated, N,N-containing bicyclic ring from piperazic acid or an ester thereof especially useful as an intermediate in the manufacture of a caspase inhibitor |
PE20011350A1 (es) * | 2000-05-19 | 2002-01-15 | Vertex Pharma | PROFARMACO DE UN INHIBIDOR DE ENZIMA CONVERTIDORA DE INTERLEUCINA-1ß (ICE) |
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WO2004026406A1 (en) * | 2002-09-20 | 2004-04-01 | Alcon, Inc. | Use of cytokine synthesis inhibitors for the treatment of dry eye disorders |
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