CN101829327A - 包含喹啉抗疟化合物和蛋白酶抑制剂的组合的药物组合物及其应用 - Google Patents
包含喹啉抗疟化合物和蛋白酶抑制剂的组合的药物组合物及其应用 Download PDFInfo
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- CN101829327A CN101829327A CN200910207930A CN200910207930A CN101829327A CN 101829327 A CN101829327 A CN 101829327A CN 200910207930 A CN200910207930 A CN 200910207930A CN 200910207930 A CN200910207930 A CN 200910207930A CN 101829327 A CN101829327 A CN 101829327A
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- malaria
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Abstract
本发明涉及包含喹啉抗疟化合物和蛋白酶抑制剂的组合的药物组合物及其应用。本发明涉及在AIDS和疟疾的治疗中能够带来治疗益处的药物组合物。具体而言,本发明涉及包括至少一种喹啉抗疟化合物,诸如氯喹或羟化氯喹,以及至少一种人免疫缺陷病毒(HIV)蛋白酶抑制剂的药物组合物。该药物组合物能够抑制HIV和疟原虫的复制。本发明还涉及HIV PIs的直接抗疟效果。
Description
本申请是2004年2月20日提交的题目为“利用氯喹和蛋白酶抑制剂的组合物治疗HIV或疟疾的方法”的中国专利申请200480004877.2(对应国际申请PCT/US2004/005122)的分案申请。
本申请要求2003年2月21日提交的临时专利申请No.60/449,517和2003年5月16日提交的临时专利申请No.60/471,038的优先权,这两篇临时申请的内容在此以其全文引作参考。
发明领域
本发明涉及在获得性免疫缺陷综合症(AIDS)和疟疾的治疗中能够带来治疗益处的药物组合物。具体而言,本发明涉及包括能够抑制人免疫缺陷病毒(HIV)和疟原虫复制的氯喹或羟化氯喹以及HIV蛋白酶抑制剂的药物组合物。本发明还涉及HIV蛋白酶抑制剂的直接抗疟效果。
发明背景
获得性免疫缺陷综合症(AIDS)和疟疾是侵袭人类最严重的传染病之一,每年导致全世界近500万人死亡。在不发达国家,这些病的最显著影响在于疾病伴随着原本已悲惨的财政和生活条件。数个资源贫穷的国家负担不起有效的治疗,这些治疗有可能防止许多疾病的死亡。既治疗AIDS又治疗疟疾的难度本身部分是由于两者病原的抗药性造成的,即,人免疫缺陷病毒(HIV)和原生动物同属于疟原虫属,在药物武器极度受限时变得言过其实。在数个HIV血清流行率高的资源贫穷国家,使用高活性抗逆转录病毒治疗(HAART)遇到的主要障碍是其高成本和处方的复杂性。最近,出于人道主义考虑,抗-HIV药物已经以低价提供至HIV血清流行高的最不发达国家。然而,问题远未得以解决。与抗逆转录病毒药比较,抗疟药的成本较低,无论如何这可能加重这些贫穷国家的支出。氯喹(CQ)作为世界卫生组织(WHO)长时间以来推荐的第一线治疗疟疾药,在非洲仍然是最负担得起和最广泛采用的抗疟药选择,不过,连续出现抗药性的疟原虫株使得在非洲,拉丁美洲和东南亚的大片地区给药无效。
由于大多数受AIDS病重创的地区还表现出地方性疟疾(并且通常个体是共感染),因此开发针对这两种疾病有效的治疗将是有用的。
在这方面,CQ可能特别有用,因为其已显示体外抗HIV-1复制和抗若干种AIDS-相关机会微生物的活性。它还充分证明当用于无免疫应答的个体为抗疟预防服药和用于治疗风湿病中时是长期安全的。尽管未获得CQ对病毒量的体内影响的信息,但其羟基类似物,羟化氯喹(HCQ)已证明有体内抗-HIV-1活性。CQ的抗-HIV活性归功于用药物处理的细胞所产生的病毒粒子传染性的损害。虽然本发明不限于任何具体的机制,但据认为该抑制作用背后的机制是因为gp120糖基化的抑制。这种假设得到了下列结果的支持:CQ损害了严重糖基化表位2G12的形成,所述表位位于gp120包膜蛋白表面,对病毒传染性至关重要。这些作用表明,通过不同于现用的抗逆转录病毒药物的机制,CQ抑制病毒复制,而这种新机制已导致CQ与抗逆转录病毒药组合在临床试验中进行测试。
CQ抗-HIV效果更详细的信息可在下列两篇文章中找到,在此以其全文并入本专利申请中:
Savarino A,Gennero L,Chen HC,Serrano D,Malavasi F,BoelaertJR,Sperber K.氯喹的抗-HIV作用:抑制机制和活性谱(Anti-HIV effectsof chloroquine:mechanisms of inhibition and spectrum of activity)。AIDS2001 Nov 23;15(17):2221-9。
Savarino A,Gennero L,Sperber K,Boelaert JR.氯喹的抗-HIV-1活性(The anti-HIV-1 activity of chloroquine)。J Clin Virol 2001 Feb;20(3):131-5。
已知CQ在与其他抗-HIV药物,诸如ddI,羟基脲以及AZT组合施用时,可发挥附加效应。但是直到本发明才完全知晓组合施用CQ和HIV蛋白酶抑制剂(PIs)的效果。鉴于将来在疟疾地方病区大规模给药PI基的疗法,该相互作用可提供下列现象:1)CQ/HCQ和PIs是在人中测试的整合后阶段抑制HIV复制的唯一药物;2)GQ和PIs两者的作用皆导致损害新生病毒粒子的传染性;3)CQ和PIs是重要细胞表面药物转运蛋白的底物,并且在不同水平抑制该转运蛋白,所述转运蛋白即P-糖蛋白(P-gp)和多药抗性相关蛋白(MRP),它们属于ATP-结合盒家族,并调节抗逆转录病毒药物的胞内浓度。有意义的是,最近的数据显示CQ能够增加由PIs施加的P-gp-和MRP-介导的流出在CD4+淋巴细胞中的抑制水平(Savarino等,JAIDS 2004,待出版)。
PIs对细胞表面药物转运蛋白的抑制作用使得CQ和PI的组合尤其可用于治疗疟疾。
药物在细胞表面上的运输已被假设参与疟原虫药物抗性。该理论得到了数件证据的支持。
首先,恶性疟原虫(P.Falciparum)的糖蛋白,即Pf-MDR,与人P-gp具有高度的同源性,并且在有些途径上相关于CQ-抗性。Ward SA,BrayPG.Pfmdr 1在恶性疟原虫喹啉抗性中的作用的确定证据(Definitiveproof for a role of pfmdr 1 in quinoline resistance in Plasmodiumfalciparum).Drug Resist Updat 2000 Apr;3(2):80-81。
其次,体外CQ-抗性特征性地被戊脉安回复,戊脉安是人细胞中ATP-结合盒的已知抑制剂。Sidhu AB,Verdier-Pinard D,Fidock DA.通过pfcrt突变赋予的在恶性疟原虫(Plasmodium falciparum)疟疾寄生虫中的氯喹抗性(Chloroquine resistance in Plasmodium falciparum malariaparasites conferred by pfcrt mutations).Science 2002 Oct 4;298(5591):210-3。
第三,被CQ-抗性恶性疟原虫(P.Falciparum)株寄生的红血球比被CQ-敏感菌株寄生的累积更有限的胞内CQ池。恶性疟原虫(P.Falciparum)株在红细胞内降低CQ累积的能力严格相关于编码所谓的CQ抗性转运(CRT)蛋白的基因(Pf-crt)突变。恶性疟原虫(P.Falciparum)CRT介入这些现象的确切机制尚未加以阐明。有意义的是,这些突变存在于绝大多数来自世界突变地区的CQ抗性野外分离株中,而不存在于CQ-敏感的分离株。Sidhu AB,Verdier-Pinard D,Fidock DA.通过pfcrt突变赋予的在恶性疟原虫(Plasmodium falciparum)疟疾寄生虫中的氯喹抗性(Chloroquine resistance in Plasmodium falciparum malariaparasites conferred by pfcrt mutations).Science 2002 Oct 4;298(5591):210-3。
具有既抑制HIV又抑制疟原虫的CQ和PI的组合物以及利用该组合物治疗将是有益的。
发明概述
本发明涉及在AIDS和疟疾的治疗中能够带来治疗益处的药物组合物。具体而言,本发明涉及包括HIV蛋白酶抑制剂加上CQ或HCQ或另一具有相似特性的抗疟药的药物组合物。该药物组合物既然能抑制HIV复制又能抑制疟原虫复制。本发明还涉及HIV PIs的直接抗疟效果。
本专利申请所保护的组合物出乎意料地证明了比单独施用单一药剂给予更持久的既抑制HIV又抑制疟原虫的能力,即,CQ可加强PI的抗逆转录病毒活性,而PI可加强CQ的抗疟活性。
因此,PI加上CQ的组合物可用于抑制HIV复制的目的,用于抑制疟原虫生长的目的,或用于抑制这两种致病因子的目的。
从临床角度看,PI加上CQ/HCQ的组合物也许能够治疗AIDS和疟疾。因此,其可用于治疗感染有HIV的个体,受疟疾侵袭的个体或处于接触疟疾风险中的个体,或HIV/疟疾共感染的人们。
同样,CQ和PIs的组合物可用来恢复HIV和恶性疟原虫(P.Falciparum)抗药性分离株分别对PIs和CQ的灵敏度。
在另一实施方案中,本发明涉及PIs固有的抗疟作用。本发明人发现,PIs临床上用于治疗HIV具有直接抗疟效果。这些直接效果以治疗上可实现的浓度在体外是可观察的(参见实施例III)。
尽管本发明不涉及任何特定的机制,但生物信息学分析提示,PIs的靶可能是plasmepsin II,其为plasmepsins家族成员,新抗疟药的潜在靶。
附图详述
图1和2示出利用VAST算法(可得自NCBI网址,http://www.ncbi.nlm.nih.gov)得到的三维结构叠印和恶性疟原虫(P.Falciparum)plasmepsin II和HIV-1蛋白酶之间相应的序列比对。plasmepsin II的三维结构得自蛋白数据库(PDR;http://rcsb.org/pdb/)。所示HIV-1蛋白酶为通过提交plasmepsin II结构至NCBI数据库用于检索结构相近物而寻找到的许多逆转录病毒蛋白酶序列之一。因此,它的示出仅仅是个例子,并非旨在以任何方式限制本发明的范围。
图1示出恶性疟原虫(P.Falciparum)plasmepsin II和HIV-1蛋白酶比对结构域的三维结构叠印的两种不同图象。显著比对和相应于两分子催化位点的残基由点标记(......)表示。比对水平较低的plasmepsin II区域由十字线标记(××××)表示。HIV蛋白酶的相似区域由虚线(---)表示。PI茚地那韦(Indinavir)(IDV)在HIV-1蛋白酶的复合物中的分子结构也以暗阴影区域显示。
图2显示对应于图1所示三维比对的序列比对。残基上下所示标记严格对应于图1中标记,并且在上节中说明。没有任何对应标记的区域对应于未比对的结构域(图1中未示出)。
图3显示CQ和HIV PIs对病毒复制的组合影响。简而言之,MT-4细胞或初级外周血单核细胞(PBMC)分别用实验室株或初级分离株接种。然后,HIV感染的细胞与选定浓度的IDV和/或CQ温育。
图3A显示在IDV存在下,CQ对HIV-1 IIIB在MT-4细胞中复制的影响,其中表明在CQ+IDV存在下HIV-1p24产量的降低(平均值±S.E.M.;三次实验)。在此情形下,细胞以低感染复数(0.01)感染,旨在更好地揭示IDV/CQ组合对HIV-1复制具有任何有利的影响。
图3B的isobologram证明CQ+IDV组合抗HIV-1IIIB复制的分抑制浓度。CQ+PI组合的分抑制浓度显示能够抑制病毒复制90%(EC90)。依据非线性回归模型,计算出最佳拟合数据点的曲线。该图形示出在简单加成效果(在x和y轴上连接1.0FIC)以及亚协同和实际协同效果之间阀值(即,连接0.5FIC值的线)的情形下预计的线。
图3C示出的isoboles证明CQ+沙奎那维(saquinavir)(SQV)和CQ+利托那韦(ritonavir)(RTV)抗HIV-1IIIB复制的分抑制浓度。如在前幅图中一样,该图显示导致EC90的CQ+PI的FIC。呈现的线和曲线如前段中所述获得。
图3D示出在存在或缺乏CQ下对初级分离株(VI829,HIV-1CladeC)的反应增强。在该图以及下列图中,病毒复制以未处理对照的百分比表示,以便容易比较IDV在存在和缺乏CQ(1μM)下的效果。CQ-处理和未处理培养物之间的差异从回归线是显而易见的,所述回归线最佳匹配数据点并在IDV的EC50中导致近1Log的差异(标记在图中)。
图3E示出通过CQ部分恢复对来自HIV-1Clade B的PAVIA12多药抗性分离株中的IDV的反应。
图3F示出通过CQ部分恢复对属于HIV-1 Clade A的分离株的IDV的反应。该分离株(UG3)类似于一些PI抗性病毒,病毒复制峰出现在PI中间浓度下。从该图中,CQ显然促使IDV-诱导的病毒复制峰值向PI最低nM浓度的位移。在CQ存在下峰振幅较低极可能归因于抗疟药直接抗-HIV效果。
图4示出HIV蛋白酶抑制剂RTV和IDV对实验室疟原虫株(3D7)和野外分离株(Ibginovia)的影响。结果以对照值的百分比表示。
图5A示出HIV-1蛋白酶抑制剂利托那韦组合CQ对CQ-抗性恶性疟原虫(P.Falciparum)野外分离株(Ibginovia)的影响。为了阐述典型结果,如实施例部分材料和方法中所述,在由疟原虫乳酸脱氢酶(LDH)介导的反应结束时,数据表示成平均值±S.D.光密度(O.D.)。O.D.值与恶性疟原虫(P.Falciparum)细胞存活率成正比。
图5B示出IDV(5μM)组合CQ对CQ-抗性恶性疟原虫(P.Falciparum)株(W2)的影响。结果以对照值的百分比表示。
图5C示出IDV(5μM)组合CQ对CQ-敏感的恶性疟原虫(P.Falciparum)株(3D7)的影响。结果以对照值的百分比表示。
图6为RTV在感染有伯氏疟原虫(Plasmodium berghei)的小鼠中的抗疟效果。
图6A为RTV(50mg/kg)对伯氏疟原虫(P.Berghei)在Balb/c小鼠中生长的影响。结果表示成不同随访天数寄生的红血细胞百分比的平均值±S.D.。
图6B为RTV(50mg/kg)对感染有伯氏疟原虫小鼠存活率的影响。结果表示成Kaplan Meyer曲线,并以P值报告存活率的差异。
图6C为RTV(150mg/kg)对伯氏疟原虫在Balb/c小鼠中生长的影响。结果表示成不同随访天数寄生的红血细胞百分比的平均值±S.D.。
图6D为RTV(150mg/kg)对感染有伯氏疟原虫小鼠存活率的影响。结果表示成Kaplan Meyer曲线,并以P值报告存活率的差异。
发明详述
本发明涉及有效针对世界上两种主要传染病,即AIDS和疟疾致病因子的药物组合物。具体而言,本发明涉及包括既能抑制HIV复制和又能抑制疟原虫复制的HIV蛋白酶抑制剂加上抗疟药,诸如CQ或HCQ的药物组合物。
本专利申请中要求保护的组合物能够比单一成分独自给药对HIV和疟原虫给予更持久的抑制,即,CQ可加强PI的抗疟活性,而PI可加强CQ的抗疟活性。
由于上述组合物对HIV和疟原虫皆可见治疗效果,组合物可用于抑制HIV复制的目的,用于抑制疟原虫生长的目的,或用于既抑制HIV复制又抑制疟原虫生长的目的。
从临床角度,PI加上抗疟药,诸如CQ/HCQ的组合物可用于治疗AIDS和疟疾。因此,所述组合物可用于治疗感染有HIV的个体,受疟疾侵袭或处于接触疟疾风险的个体,或患有HIV/疟疾共感染的人们。这两种用于组合物中的组分可增加药物敏感性HIV的抑制水平,并且PI+CQ组合恢复了HIV和恶性疟原虫(P.Falciparum)抗药性分离株分别对PIs和CQ的灵敏度。
关于HIV的治疗,重要的是指出,CQ组合蛋白酶抑制剂的效果是协同的。当与PI组合给药急性感染的细胞时,CQ降低了产生一定程度的HIV抑制所必需的PI浓度[参见实施例1]。
此外,如下举例,CQ部分恢复了对PIs在PIs抗性株中的灵敏度[参见实施例1]。
尽管本发明不限于任何特定的机制,据认为使用P-gp和MRP阻断剂,诸如CQ,可增加PIs的胞内浓度。
在一个实施方案中,本发明给予治疗策略,由此给HIV阳性个体共施用抗疟药,诸如CQ/HCQ或另一喹啉药剂使得PIs的有效剂量降低,成本和可能的毒性减少。同样,CQ克服对PIs抗性的能力在治疗药物体验的HIV阳性对象方面具有重要意义,该阳性对象已发展对抗逆转录病毒药物的多抗性,从而具有受限的治疗选择。
本发明的实施方案也可用于治疗抗药性疟疾。事实上,在世界数个地方性疟疾的区域,具有多药抗性表型的恶性疟原虫(P.Falciparum)株正变得流行,并且使用PI可恢复对CQ的灵敏度。因此,这样一种药物的实用性预计可挽救众多的生命。在目前买不起PIs的第三世界地区,当PIs用于大规模治疗HIV感染时,成本问题有望在不久的将来至少部分得以解决。考虑到AIDS和疟疾经常共存于同一区域,PIs有可能比它们现在更常用于上述地区,并因此假设在治疗疟疾中更经济有效地使用这些药物。同样,生活在地方性抗药性疟疾地区并用PI+CQ组合物治疗的HIV-感染个体可防止疟疾事件的发生。
而且,PIs组合喹啉药剂的所述效果可有助于药物,诸如CQ和第一代PIs(RTV,SVQ,IDV)的复活,这些药物原本在不久的将来注定会被更新的药物替换。
总而言之,本发明涉及施用对HIV和疟疾有效的药物组合物。组合物的实施方案包括:
1)氯喹(CQ)或羟基氯喹(HCQ)或另一喹啉药剂,诸如甲氟喹(Mefloquine)(MQ)和奎宁(quinine)(Q)
组合有
2)一种或多种HIV蛋白酶抑制剂(PIs)。
PIs包括:
茚地那韦(IDV),利托那韦(RTV),沙奎那维(SQV),奈非那韦(nelfinavir)(NFV),洛匹那韦(lopinavir)(LPV),RTV加上LPV的组合,安普那韦(amprenavir)(APV),福沙那韦(fosamprenavir)(FPV),替拉那韦(tipranavir)(TPV),阿扎那韦(atazanavir)(ATZ),TMC-114。
抗疟药和PI组合物可与HIV反转录酶的核苷抑制剂(NRTI)一起同时共给药。
NRTIs包括:
齐多夫定(Zidovudine)(AZT或ZDV),拉米呋啶(lamivudine)(3TC),阿巴卡韦(abacavir)(ABC),扎西他滨(zalcitabine)(ddC),去羟机苷(didanosine)(ddI),司他呋啶(stavudine)(d4T),泰诺福韦(tenofovir)(TDF),emitricitabine(FTC),amdoxovir(DAPD)。
本发明不受限于此方面,任何合适的喹啉药剂,PI和/或NRTI皆可使用。
抗疟药和PI组合物也可与其他抗疟药,或与针对伴随感染的抗生素,或与针对共存或相关疾病的任何药物一起同时共给药。
本发明还涉及HIV PIs的直接抗疟作用。不仅PIs可回复CQ抗性,而且PIs也赋有固有的抗疟作用。这些直接作用在体外以治疗可实现的浓度(参见实施例II)和在鼠疟疾模型的体内(参见实施例III)是可观察到的。
PIs直接抗疟作用的机制尚未阐述。然而,有趣的认识来自下列观察结果:HIV-1蛋白酶(即,针对靶设计的这些药物)与疟原虫plasmepsins家族成员的蛋白酶享有显著的序列-和结构-相似性(图1和图2)。与HIV-1蛋白酶相似,plasmepsins是天冬氨酰蛋白酶,并在恶性疟原虫(P.Falciparum)的胞内生长中具有基本作用。它们参与血红蛋白降解的第一步,所述血红蛋白构成寄生虫的红细胞内阶段的主要营养物。鉴于HIV-1蛋白酶和plasmepsins之间的结构相似性,有可能假设PIs通过靶向这些酶损害疟原虫生长。该假设由下列事实维持:两蛋白间最大相似性的区域在于其催化位点,该位点在HIV-1蛋白酶中非共价结合于PIs并被PIs抑制。如果该机制得到实验数据证实,HIV PIs作为第一药物在人体中进行安全测试,以抑制plasmepsins家族成员,最近由WHO指定成开发新抗疟药的潜在靶。在抗药性疟原虫株连续出现的时间,涉及新靶的药物的药库的可用性增加药物选择。PI抗疟作用的其他潜在的依据是最近所述的通过这些药物在人红细胞中诱导的下调CD36(恶性疟原虫(P.Falciparum)的受体)。Nathoo S,Serghides L,KainKC.HIV-1抗逆转录病毒药物对细胞附着和吞噬清除恶性疟原虫(Plasmodium falciparum)-寄生的红细胞的作用(Effect of HIV-1antiretroviral drugs on cytoadherence and phagocytic clearance ofPlasmodium falciparum-parasitised erythrocytes)。Lancet.2003 Sep 27;362(9389):1039-41。
上述机制的说明仅为解释性目的:本发明涉及PIs对疟原虫体外和体内生长的影响,并不限于任何特定的机制。
如上所述,PI的直接抗疟作用巩固了它们与CQ的组合使用。PIs的直接抗疟作用也表明,生活在地方性疟疾的区域并用包括PI的抗逆转录病毒鸡尾酒治疗的HIV-感染的个体,至少部分防止疟疾事件的发生。考虑到数个贫穷国家有限的支出,防止疟疾事件对治疗HIV而言是有利的。事实上,在次撒哈拉非洲(Sub-Saharian Africa),有疟疾地方性病的区域,HIV血清流行性水平可抵达30%。由于HIV-感染的人们处于高风险的复杂疟疾,可以想象PI的直接抗疟原虫作用可拯救大批人类和节省财政资源。
本发明将通过实施例进一步加以描述,这些实施例用于帮助本领域普通技术人员实施本发明,并不旨在以任何方式限制本发明的范围。
实施例
材料和方法
感染分析
使用实验室适合的HIV-1IIIB和HIV-2CBL/20株,初级分离株HIV-1UG3(Clade A,R5)和HIV-1VI 829(Clade C,R5),皆得自抗逆转录病毒幼稚对象。这些病毒充分描述在Savarino A.等(同上)的论文中。还使用HIV-1PAVIA12分离株,由Maurizia Debiaggi博士,University of Pavia,Italy馈赠,Maurizia Debiaggi博士也进行了其基因型分析。HIV-1PAVIA12分离株属于Clade B并分离自患有HAART衰竭的个体,其对所有类型当前医学实践中所用的抗逆转录病毒具有多药抗性的基因型图谱(HIV-1反转录酶中的突变:67N 69D 70R 74V 108I 181C 184V 219Q228R;HIV-1蛋白酶中的突变:10I 20R 36I 46L 54V 55R 63P 71V 82A90M)。利用MT-2细胞(实验株)或PHA-活化的外周血单核细胞(PBMC)(初级分离株),通过50%终点稀释法生物学滴定病毒原种。
在急性感染分析中,将合适类型的细胞与感染复数(MOI)近0.1的病毒原种在37℃温育2小时,除非另有规定。三次洗涤后,细胞在新鲜培养基中37℃温育7天,感染后不同间隔时间收集无细胞悬浮液用于ELISA测量HIV-1p24(NEN Life Science Prod.,Boston MA)或HIV-2p27(Coulter,Hialeah,FL)(26,33)。接着在病毒吸附后,细胞在CQ治疗个体的血浆中可达到的CQ浓度下温育。
选择性指数计算成IC50/EC50比。在感染PBMC的情况下,对各个供体绘制毒性曲线,以精确估计选择性指数。
CD4+CXCR4+MT-4T-细胞系用于评价CQ和PIs对X4实验室适合的株的影响,然而利用初级分离株,在分析中采用通过知情同意从健康供体中获得并以2pg/ml植物血球凝集素(PHA;Difco Laboratories,Detroit,MI)刺激3天的外周血单核细胞(PBMC)。
有关模仿的病毒学程序的更详细信息可在下列文章中找到:Savarino A,Gennero L,Chen HC,Serrano D,Malavasi F,Boelaert JR,Sperber K.氯喹的抗HIV作用抑制机制和活性谱:(Anti-HIV effects ofchloroquine:mechanisms of inhibition and spectrum of activity)。AIDS2001 Nov 23;15(17):2221-9,在此以其全文引作参考。
毒性评价分析
在未感染的对照中,细胞存活率和程序性死亡通过本发明人先前验证的技术所确定的台盼蓝排阻法,MTT法,和碘化丙锭/annexin VFITC染色进行分析。有关模仿的病毒学程序的更详细信息可在下列文章中找到:Andrea Savarino,Thea Bensi,Annalisa Chiocchetti,FlaviaBottarel,Riccardo Mesturini,Enza Ferrero,Liliana Calosso,SilviaDeaglio,Erika Ortolan,Stefano Butto,Aurelio Cafaro,Toshiaki Katada,Barbara Ensoli,Fabio Malavasi,和Umberto Dianzani(2003)通过序列同源于病毒包膜糖蛋白gpl20的V3环,人CD38干扰HIV-1融合(HumanCD38 interferes with HIV-1 fusion through a sequence homologous to theV3 loop of the viral envelope glycoprotein gpl20)。The FASEB JournalExpress Article 10.1096/fj.02-0512fje,在此以其全文引作参考。
协同性评估
为了测量协同性,在病毒吸附到细胞上后,细胞沉淀重悬于含有不同组合的CQ和IDV的培养基中。然后,分抑制浓度(FIC)计算成药物A的药EC90与单独药物B的药物2/EC90的组合。当FICs之和<0.5时,效果视为协同。
寄生虫
Ibginovia为从the Istituto Superiore di Sanita,Rome,Italy获得的分离株,对赋予CQ抗性的pfcrt基因中的密码子K76和A220突变是阳性的。该寄生虫来自尼日利亚。所有寄生虫体外维持在RPMI 1640培养基中,其中加入人A型红血细胞(RBC)和10%热灭活人血清。所有培养物置于加湿培养箱中,37℃,3%O2,6%CO2,和91%N2的气体控制环境,并且依据现成的程序饲喂。
寄生虫血症的检测
利用Giemsa染色的稀薄涂片通过可见光显微镜和利用染料硫代苯并羧嘌呤通过荧光显微镜确定寄生虫血症。
寄生虫乳酸脱氢酶测量
该分析是基于下列原理:疟原虫乳酸脱氢酶(LDH)可利用3-乙酰吡啶NAD(APAD)作为辅酶,APAD在乳酸氧化过程中转化成APADH。所有LDH确定的样品在650nm处通过分光光度法测量。为这些测量,10-50μl的疟疾样品加入到Mastat试剂中,该试剂为寄生虫LDH检测的优化配方。样品由疟疾培养物组成。利用96孔微量滴定板,所有等份试样加入到0.2ml的Malstat试剂。利用多波长板读数仪,在650nm处确定APADH的形成。测试微量滴定板的各孔以30秒间隔进行自动化测量,以及单个数据点储存,并随后用软件程序绘制。LDH活性的分光光度计评价通过加入NBT(0.24mM)和PES(0.033mM)至Malstat试剂得以促进。随着APADH形成,NBT减少,形成蓝色甲(formazan)产物,并肉眼检测和在650nm处测量。该分析特异于寄生虫LDH,不受人酶的影响。Makler MT和Hinrichs DJ(1993)恶性疟原虫(Plasmodium falciparum)的乳酸脱氢酶活性的测量作为寄生虫血症的评估(Measurement of lactate dehydrogenase activity of Plasmodiumfalciparum as an assessment of parasitemia)。Am J Trop Med Hyg48:205-10。
实施例I
该测试的目的是分析加入CQ至IDV是否比IDV单独产生更高的HIV抑制水平。HIV-1IIIB-感染的MT-4细胞在存在或缺乏增加浓度CQ(1-6.25μM)下温育在含有10nM IDV的培养基中。所选IDV浓度接近于HIV-1IIIB-感染的MT-4细胞中的EC50,如同在本实验条件下测定一样(数据未显示)。加入CQ未导致细胞存活率的显著差异,从而排除所观察的差异是由于特异性损害通过CQ施加的细胞存活率(数据未显示)。感染后5天,在用CQ+IDV处理的培养物的上清液中p24水平比单独用IDV处理的细胞上清液的低(图3A;P<0.05,重复测量ANOVA)。CQ的作用是剂量依赖的,这提示CQ/IDV组合的抗HIV-1效力降低CQ浓度增加的平行性。
为了更好地探索这种现象,确定不同CQ/IDV组合的作用以评价组合的作用是否是加成的,协同的或亚协同的。HIV-1IIIB-感染的细胞以多种不同浓度的CQ或IDV单独或组合处理。测试以评价各药物在产生90%HIV-1复制抑制的不同组合物中的浓度。对于各药物组合物而言,确定FIC。利用isobolograms法分析显示,CQ对IDV的抗HIV-1活性的作用在低CQ的FICs时是协同的(对应于预防抗疟血浆浓度,即,0.1-1μM,在中间浓度FICs(≈3.12-6.25μM)是亚协同或加成的,以及在最高CQ的FICs(≈≥10μM,临床上非相关浓度)时是稍拮抗性的。相似作用以HIV-2获得(数据未显示),和利用CQ与RTV或SQV组合获得(图3B)。结果显示,在疟疾预防过程中发现的CQ浓度在与PIs组合后施加协同抗HIV作用。然后,测试CQ处理对初级HIV分离株易感于IDV的影响。为此目的,在存在或缺乏1μM的CQ下,PHA-刺激的外周血单核细胞(PBMC)感染有初级HIV-1分离株,洗涤,并与增加浓度的IDV(0-1000nM)温育。结果表明,5天上清液中p24的水平在用IDV+CQ处理的培养物中比在用匹配IDV浓度但无CQ处理的培养物中更低。图3D显示CQ对属于亚型C(VI 829)的IDV-敏感性分离株的典型作用。在此情形下,CQ降低了EC50近1Log。而且,CQ部分恢复了对IDV在多抗性HIV-1分离株中的反应(图3E)。接着,测试了IDV/CQ组合对属于“西非”HIV-1亚型A的分离株(UG3)的作用。通过UG3分离株感染后5天,与100nM IDV温育的细胞呈现出p24水平在上清液中的典型峰,类似在相似PI浓度存在下来自亚型B的PI-抗性粒子所述的传染性增加。Mammano F,Trouplin V,Zennou V,Clavel F.回溯人免疫缺陷病毒型1对蛋白酶抑制剂抗性的进化途径:在药物缺乏和存在下病毒适宜(Retracing the evolutionary pathways of humanimmunodeficiency virus type 1 resistance to protease inhibitors:virusfitness in the absence and in the presence of drug)。J Virol.2000 Sep;74(18):8524-31。利用1μM的IDV,反而可见抑制效果。利用自100nM开始的IDV,在CQ存在下,恢复位移至最低nM IDV浓度(远低于临床上所达到的那些浓度)的p24水平峰和抑制(图3F)。整体上,这些结果符合CQ对IDV反应的协同效果。事实上,它们不能归因于唯一加成效果的在于,在1μM浓度的单独CQ的抑制作用是最低的(数据未显示)。
这些差异不可能有助于通过CQ+IDV组合物施加的毒性作用,如同用1μM CQ处理的PBMC的细胞存活率值基本上与在CQ缺乏下用相同IDV浓度处理的细胞的那些值相同一样(数据未显示)。
实施例II
在对CQ+PIs结合进行实验之前,评价了蛋白酶抑制剂当单独给药至恶性疟原虫(P.Falciparum)寄生的红细胞时的效果。恶性疟原虫(P.Falciparum)-寄生的红细胞(开始寄生虫血症≈1%)与IDV和RTV浓度培育48小时,所述浓度位于以这些PIs处理的个体中在临床上可观察到的范围之内。接着收集红细胞悬浮液的等份试样,并分析恶性疟原虫(P.Falciparum)LDH活性。结果显示,RTV和IDV剂量依赖性地抑制恶性疟原虫(P.Falciparum)生长(图4),恶性疟原虫(P.Falciparum)-寄生的红细胞在存在或缺乏PI下与浓度增加的CQ培育48小时,然后分析恶性疟原虫(P.Falciparum)LDH活性作为细胞存活率的量度。图5A和图5B以组合PI和CQ获得的典型结果。从这些数据中,显然RTV和IDV在CQ-抗性恶性疟原虫(P.Falciparum)中恢复对CQ的反应,当这些PIs使用浓度为本身亚最适抑制恶性疟原虫(P.Falciparum)生长。在CQ-敏感性恶性疟原虫(P.Falciparum)株(3D7)中,IDV对CQ反应的作用是较不显著的,如图5C所示。
为了确定CQ+PI组合物的效果是否仅是加成或协同的,本发明人利用FICs之和的方法,分析了W2(CQ-抗性)和3D7(CQ-敏感的)株对IDV的反应。这些分析报告了对W2株的值≤0.5(指示协同效果),而对3D7株值>0.5。由于协同效应仅在CQ-抗性株而非在CQ-敏感性株中观察到,结论是IDV恢复对氯喹的灵敏度。因此,对CQ-抗性株的效果不仅归因于将IDV与CQ的效果加成。
整体上,这些结果表明,PIs以averapamil-样方式回复CQ-抗性。
实施例III
为了评价PI在疟疾动脉模型中的效果,Balb/c小鼠腹膜内接种有伯氏疟原虫(P.Berghei),然后分成三组:1)胃内接种磷酸盐缓冲液(PBS)处理的模拟物,2)在利托那韦(安慰剂)缺乏下胃内用利托那韦稀释剂(即,47%醇溶液)处理,以及3)胃内用50或150mg/kg处理。经确定利托那韦(处理1)剂量依赖性地延迟了寄生虫在小鼠中的增殖,由此处理2和3没有相似的作用(图6A和6C)。有意义的是,根据图6B和6D中所示的Kaplan-Mayer曲线,利托那韦也以显著方式增加了处理小鼠的存活率。
实施例IV
利用本领域技术人员公知的技术给药抗疟/PI组合物。抗疟药/PI组合可以药物组合物施用,包括适当的赋形剂,稀释剂或载体。给药抗疟药/PI组合物推荐的途径包括口服,肌内,经皮,舌下,静脉内或皮下方法。
药物组合物的形式可为同于传递药物组合物的片剂,糖衣,胶囊,药丸,溶液,悬浮液,乳液或任何其他适当的形式。固相形式的药物组合物可含有非水性稀释剂或载体,包括例如,填充剂,增补剂,结合剂,保湿剂,崩解剂,表面活性剂,吸附载体,润滑剂,或任何其他对本领域技术人员公知的合适的稀释剂或载体。液相形式的药物组合物包括稀释剂,或载体,诸如,水,乙醇,丙二醇或任何其他合适对本领域技术人员公知的稀释剂或载体。对于肠胃外施用而言,溶液和悬浮液应是无菌的,并且如果合适,应是血液等渗的。
如在此所用,术语“治疗有效量”表示抗疟药/PI组合物会抑制HIV复制和/或疟原虫的剂量。治疗有效量可根据标准医学原理在医师指导下确定。CQ和PI可以任何适当的给药形式,诸如药物可接受的盐提供。
在预防性治疗疟疾中,所用PIs的剂量将取决于治疗所选的PI,以及PI是否单独使用还是与其他抗疟药组合使用。用于治疗疟疾所施用的PI剂量范围是用于治疗HIV施用的典型剂量的1/2至2倍。
对于治疗急性疟疾而言,所施用PI的剂量也取决于治疗所选的PI,以及PI是否单独施用还是与抗疟药组合施用。用于治疗极性疟疾所施用的PI剂量范围是用于治疗HIV施用的典型剂量的1/2至3倍。
对于抗疟预防而言,可施用CQ和PI的组合,其中CQ包含约0.8%重量(利用例如,安普那韦或沙奎那维组合中)至约15%重量(利用例如,vitonavir/洛匹那韦1∶4w/w组合中)的组合CQ/PI的总重量。施用CQ的量少于2%重量的总CQ/PI组合可允许每周一次施用CQ,而在当天定期施用分开剂型的蛋白酶抑制剂,诸如每12小时或每8小时。施用蛋白酶抑制剂和用于施用蛋白酶抑制剂所用的剂型依据是本领域技术人员公知的方法和剂型。
施用CQ的量大于2%至10%重量的总CQ/PI组合(取决于所用蛋白酶抑制剂),如上所述,可通过在单一药物剂型施用两种药物进行。在特别高水平的CQ抗性区域,所施用CQ的量可增加直至约33%重量的CQ和PI组合的总量。CQ和PI也可以单独剂型施用以在患者中实现所需剂量的CQ和PI。
对于治疗极性疟疾而言,CQ在CQ/PI组合中量可增加至约75%重量的CQ和PI组合。CQ和PI可以单独剂型施用以在患者中实现所需水平。当CQ和PI组合在单一剂型中时,在施用第一剂量的CQ/PI组合之前或同时以单一剂型单独施用额外的CQ。施用额外剂量的CQ以实现CQ合适地负载细胞。
PI用于治疗HIV的给药剂量范围为在缺乏CQ或其他抗疟药下用于治疗HIV通常给药剂量的1/4至1。
在治疗HIV感染中,CQ和PI的组合使得CQ包含约0.8%重量至约33%重量的组合CQ/PI的总重量。CQ/PI可以单一剂型施用。或者,CQ和PI以分开剂型施用以实现所需相对量的CQ和PI。
优选地,施用CQ和PI以实现CQ的血浆浓度在约0.05μM至约1μM用于治疗HIV,以及在约0.005μM至约6μM用于临床管理疟疾。优选地,施用CQ和PI以实现PI的血浆浓度在约500nm至约30μM,用于临床管理疟疾,以及在约10nM至约30nM,用于治疗HIV。本领域技术人员会认识到,本发明不限于此方面,可施用任何合适的治疗有效量的CQ和PI。
Claims (12)
1.药物组合物在制备用于治疗或预防疟疾的药物中的应用,特征在于在该组合物中包括至少一种HIV蛋白酶抑制剂或其可药用盐,其量对抑制疟原虫(plasmodium sp.)的生长治疗有效。
2.权利要求1的应用,其中所述HIV蛋白酶抑制剂选自茚地那韦,利托那韦,沙奎那维,奈非那韦,洛匹那韦,安普那韦,福沙那韦,替拉那韦,阿扎那韦,TMC-114及其组合。
3.权利要求1的应用,其中所述HIV蛋白酶抑制剂的治疗有效量包括剂量为1mg/kg体重至150mg/kg体重的利托那韦。
4.药物试剂盒,用于治疗或预防与疟疾相关的生理状况,所述试剂盒包括至少一个容器,所述容器含有至少一种HIV蛋白酶抑制剂或其可药用盐,其中所述HIV蛋白酶抑制剂在所述至少一个容器中的量由至少部分抑制疟原虫生长的治疗有效量组成,以及所述容器任选含有可药用载体。
5.权利要求4的试剂盒,其中所述HIV蛋白酶抑制剂选自茚地那韦,利托那韦,沙奎那维,奈非那韦,洛匹那韦,安普那韦,福沙那韦,替拉那韦,阿扎那韦及其组合。
6.权利要求4的应用,其中所述HIV蛋白酶抑制剂的治疗有效量包括剂量为1mg/kg体重至150mg/kg体重的利托那韦。
7.药物组合物在制备用于通过将感染有疟原虫的细胞群接触该组合物来限制疟疾流行的药物中的应用,特征在于在该组合物中包括至少一种HIV蛋白酶抑制剂或其可药用盐,其量对抑制疟原虫的生长有效。
8.权利要求7的应用,其中所述HIV蛋白酶抑制剂选自茚地那韦,利托那韦,沙奎那维,奈非那韦,洛匹那韦,安普那韦,福沙那韦,替拉那韦,阿扎那韦,TMC-114及其组合。
9.权利要求7的应用,其中所述HIV蛋白酶抑制剂的有效量为0.5mM到30mM。
10.药物组合物在制备用于通过给药于人对象或使感染有恶性疟原虫(Plasmodium falciparum)的细胞群接触组合物给基本上抗药性的恶性疟原虫株主要赋予抗疟药物灵敏度的药物中的应用,特征在于在所述组合物中包括至少一种HIV蛋白酶抑制剂或其可药用盐,其量对至少一种喹啉抗疟化合物主要赋予至少部分敏感度量有效。
11.权利要求10的应用,其中所述HIV蛋白酶抑制剂选自茚地那韦,利托那韦,沙奎那维,奈非那韦,洛匹那韦,安普那韦,福沙那韦,替拉那韦,阿扎那韦,TMC-114及其组合。
12.权利要求10的应用,其中所述HIV蛋白酶抑制剂的治疗有效量足以实现0.5mM到30mM的血浆浓度或细胞培养基浓度。
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US6265406B1 (en) * | 1998-06-30 | 2001-07-24 | Dupont Pharmaceuticals Company | Substituted quinolin-2 (1H) -ones useful as HIV reverse transcriptase inhibitors |
WO2000033654A1 (en) * | 1998-12-04 | 2000-06-15 | University Of Maryland Biotechnology Institute | Use of protease inhibitors to modulate cellular pathways, immunity and therapies associated therewith |
US20020198231A1 (en) * | 1999-07-13 | 2002-12-26 | Jodi Nelson | Compositions and methods for the treatment of Parkinson's disease |
EP1239840B1 (en) * | 1999-12-09 | 2005-04-06 | Alza Corporation | Antiviral medication |
WO2002024649A1 (en) * | 2000-09-25 | 2002-03-28 | Actelion Pharmaceuticals Ltd | Substituted amino-aza-cycloalkanes useful against malaria |
US6579898B2 (en) * | 2001-03-01 | 2003-06-17 | Pfizer Inc. | Compositions having improved bioavailability |
EP1379248A1 (en) * | 2001-04-19 | 2004-01-14 | Bristol-Myers Squibb Company | Tricyclic compounds useful as hiv reverse transcriptase inhibitors |
ITBO20020416A1 (it) * | 2002-06-28 | 2003-12-29 | Valpharma Sa | Uso della clorochina, idrossi-clorochina e derivati 4 amino-chinolinici per l'ottenimento di un farmaco per la terapia anti retrovirale atti |
-
2004
- 2004-02-20 EP EP10151499A patent/EP2189159A1/en not_active Withdrawn
- 2004-02-20 CN CN200910207930A patent/CN101829327A/zh active Pending
- 2004-02-20 CA CA2516642A patent/CA2516642C/en not_active Expired - Fee Related
- 2004-02-20 US US10/783,268 patent/US7553844B2/en not_active Expired - Fee Related
- 2004-02-20 WO PCT/US2004/005122 patent/WO2005027855A2/en active Application Filing
- 2004-02-20 EP EP04809298A patent/EP1599172A4/en not_active Withdrawn
- 2004-02-20 CA CA002676567A patent/CA2676567A1/en not_active Abandoned
- 2004-02-20 AU AU2004273773A patent/AU2004273773B2/en not_active Ceased
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2009
- 2009-05-26 US US12/472,117 patent/US20110003764A1/en not_active Abandoned
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EP2189159A1 (en) | 2010-05-26 |
AU2004273773B2 (en) | 2008-01-24 |
CA2676567A1 (en) | 2005-03-31 |
EP1599172A2 (en) | 2005-11-30 |
US20050009810A1 (en) | 2005-01-13 |
CA2516642A1 (en) | 2005-03-31 |
CA2516642C (en) | 2010-11-23 |
AU2004273773A1 (en) | 2005-03-31 |
EP1599172A4 (en) | 2006-07-26 |
WO2005027855A2 (en) | 2005-03-31 |
US20110003764A1 (en) | 2011-01-06 |
WO2005027855A3 (en) | 2006-01-26 |
US7553844B2 (en) | 2009-06-30 |
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