CN117281822A - 一种含有阿托伐醌与伊维菌素的组合物及其途 - Google Patents
一种含有阿托伐醌与伊维菌素的组合物及其途 Download PDFInfo
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- CN117281822A CN117281822A CN202311440511.0A CN202311440511A CN117281822A CN 117281822 A CN117281822 A CN 117281822A CN 202311440511 A CN202311440511 A CN 202311440511A CN 117281822 A CN117281822 A CN 117281822A
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Abstract
本发明公开了一种含有阿托伐醌与伊维菌素的组合物及其途。所述组合物含有阿托伐醌或其前药或其药学上可接受的盐作为第一活性组分,伊维菌素或其类似物作为第二活性组分。本发明还涉及上述组合物用于抑制疟原虫增殖、配子体形成的用途,其具体施用方式可以是上述活性成分的同时施用或依次施用。本发明具有如下有益技术效果:减少单一活性组分的施用量,降低潜在毒副反应的风险;协同增效,提高总体施用对疟原虫增殖、配子体形成的抑制效果。
Description
技术领域
本发明属于药物技术领域,具体涉及一种具有协同增效作用的抗疟组合物。
背景技术
伊维菌素(Ivermectin,IVM)是一种广谱、高效、低毒的体内外寄生虫杀灭药物,其主要的作用靶点为无脊椎动物肌肉和神经细胞的谷氨酸门控氯化物(GluCl)离子通道(Lynagh T,Lynch JW.Ivermectin binding sites in human and invertebrate Cys-loop receptors.Trends Pharmacol Sci.2012;33(8):432-41.),其通过高亲和力结合阻止GluCl离子通道闭合,导致氯离子内流及细胞去极化,最终致机体的麻痹或死亡。伊维菌素已被广泛应用于根除盘尾丝虫病和淋巴丝虫病的大规模给药(Mass DrugAdministration,MDA)。由于其对按蚊的强致死作用,近年来伊维菌素被考虑用于疟疾传播防控的MDA,并在与其它抗疟药联合应用的MDA临床试验中显著降低野生按蚊的存活率与人群的疟疾发病率(Dabira ED,Soumare HM,Conteh B,et al.Mass drug administrationof ivermectin and dihydroartemisinin-piperaquine against malaria in settingswith high coverage of standard control interventions:a cluster-randomisedcontrolled trial in The Gambia.Lancet Infect Dis.2022;22(4):519-528;Foy BD,Alout H,Seaman JA,et al.Efficacy and risk of harms of repeat ivermectin massdrug administrations for control of malaria(RIMDAMAL):a cluster-randomisedtrial.Lancet.2019;393(10180):1517-1526.)。实验室研究表明伊维菌素对伯氏疟原虫肝内期具有显著抑制作用,在鼠疟模型可达到与伯氨喹相近的红外期疟原虫抑制疗效(Mendes AM,Albuquerque IS,Machado M,et al.Inhibition of Plasmodium LiverInfection by Ivermectin.Antimicrob Agents Chemother.2017;61(2):e02005-16.)。在体外评价模型中,其对食蟹猴疟原虫肝内期裂殖体和休眠体的发育也有抑制作用(Vanachayangkul P,Im-Erbsin R,Tungtaeng A,et al.Safety,Pharmacokinetics,andActivity of High-Dose Ivermectin and Chloroquine against the Liver Stage ofPlasmodium cynomolgi Infection in Rhesus Macaques.Antimicrob AgentsChemother.2020;64(9):e00741-20.)。此外,在体外试验中其对恶性疟原虫红内无性期和有性期的发育同样有显著抑制作用(de Carvalho LP,Sandri TL,JoséTenório de MeloE,et al.Ivermectin Impairs the Development of Sexual and Asexual Stages ofPlasmodium falciparum In Vitro.Antimicrob Agents Chemother.2019;63(8):e00085-19.)。伊维菌素对恶性疟原虫的抑制作用被认为与其阻断疟原虫信号识别颗粒组分或某些其它核蛋白的核质穿梭有关(Panchal M,Rawat K,Kumar G,et al.Plasmodiumfalciparum signal recognition particle components and anti-parasitic effectof ivermectin in blocking nucleo-cytoplasmic shuttling of SRP.Cell DeathDis.2014;5(1):e994.)。但在随机对照的人体感染疟疾病因性预防临床试验中,单独口服伊维菌素0.4mg/kg体重剂量未能达到有效的预防作用(Metzger WG,Theurer A,Pfleiderer A,et al.Ivermectin for causal malaria prophylaxis:a randomisedcontrolled human infection trial.Trop Med Int Health.2020;25(3):380-386.)。
阿托伐醌(Atovaquone,ATO)为辅酶Q的竞争性抑制剂,可选择性地结合于疟原虫细胞色素b,抑制其线粒体电子传递链并破坏经线粒体膜电位,对红内期和肝内期疟原虫皆有抑制作用,但对肝内期休眠体无活性(Nixon GL,Moss DM,Shone AE,etal.Antimalarial pharmacology and therapeutics of atovaquone.J AntimicrobChemother.2013;68(5):977-85.)。由于阿托伐醌单药治疗会导致疟原虫快速的产生药物抗性,目前临床主要以与氯胍组成固定比例复方的形式用于无并发症恶性疟的治疗和旅行者的疟疾预防。但其在柬埔寨的使用导致了阿托伐醌抗性恶性疟的快速出现(WHOGuidelines for malaria,14March 2023.Geneva:World Health Organization;2023)。
药物抗性是全球疟疾防控面临的最大挑战。抗药性疟原虫的不断传播与扩散已导致传统一线疟疾治疗药物,如氯喹、氯胍、乙胺嘧啶、磺胺多辛-乙胺嘧啶和甲氟喹,相继失效,无法在大多数的疟疾流行地区获得90%以上的临床疗效。自2001年被世界卫生组织推荐为抗药性疟疾流行国家疟疾治疗的首选一线药物以来,以青蒿素为基础的联合疗法(Artemisinin-based combination therapy,ACT)已成为了当前最有效和临床应用最广泛恶性疟一线治疗药物。然而,随着越来越广泛的临床施用,表现为疟原虫清除速度减慢或ACT治疗失败的青蒿素抗性已在东南亚大湄公河流域地区出现广泛流行(World malariareport 2022.Geneva:World Health Organization;2022;Mathenge PG,Low SK,VuongNL,et al.Efficacy and resistance of different artemisinin-based combinationtherapies:a systematic review and network meta-analysis.Parasitol Int.),且近年来已在印度和非洲等其它流行地区出现(Das S,Saha B,Hati AK,et al.Evidence ofArtemisinin-Resistant Plasmodium falciparum Malaria in Eastern India.N Engl JMed.2018;379(20):1962-1964;Balikagala B,Fukuda N,Ikeda M,et al.Evidence ofArtemisinin-Resistant Malaria in Africa.N Engl J Med.2021;385(13):1163-1171)。恶性疟原虫青蒿素或ACT抗性的进一步发展与传播将给全球疟疾根除带来严峻挑战。为应对这一挑战,具有不同作用机制的新型抗疟药是当前的迫切需求。基于既往的疟原虫抗药发展的经验,世界卫生组织推荐以固定剂量复方的形式开发抗疟新药,以期防止或延缓疟原虫药物抗性产生、发展。此外,药物对疟原虫生命周期其它阶段的影响,如配子体的形成与存活、药物的半衰期、临床疟原虫血症的清除效率和临床施用剂量,也被视为优先研发复方药物的考虑因素。
基于此,提出本发明。
发明内容
本发明提供了一种含有阿托伐醌或其前药或药学上可接受的盐作为第一活性成分,伊维菌素或其类似物作为第二活性成分的组合物。
其中,所述阿托伐醌((3-[4-(4-氯苯基)环己基]-4-羟基萘-1,2-二酮))可以呈游离酸的形式(如式1所示),也可以呈药学上可接受的盐(如钠盐、钾盐)的形式。
其中,所述伊维菌素为伊维菌素B1a、伊维菌素B1b(式2)或它们的混合物,优选含伊维菌素B1a和伊维菌素B1b的混合物,更优选伊维菌素B1a含量高于85%、伊维菌素B1a和伊维菌素B1b总含量高于90%的混合物。
根据本发明,上述组合物对疟原虫红内期增殖、配子体形成的抑制具有显著协同增效作用,即组合物可获得比单一组分更好的抑制效果。
本发明也涉及在上述组合基础上进一步含有其它抗疟活性成分作为第三组分的组合物;
所述作为第三组分的其它抗疟活性成分包括,但不限于青蒿素、其衍生物或它们在药学上可接受的盐;
其中,所述青蒿素衍生物为二氢青蒿素、蒿甲醚或青蒿琥酯;
所述青蒿琥酯为二氢青蒿素半琥珀酸酯(式3)或其药学上可接受的盐(如钠盐、钾盐):
本发明还涉及上述组合物用于抑制疟原虫增殖、配子体形成的用途,其具体施用方式可以是上述活性成分的同时施用或依次施用;
在活性成分同时施用的情况下,可将两种或三种活性成分组合在单独的药剂形式(固定组合,如单个药片或药囊等)之内。无论是否将活性成分同时、非同时、或部分同时(三种活性成分的情况下)施用,两种或三种活性成分可以以不同的药剂形式呈现。这种情况下,本发明所涉组合可以以组合包装药剂的形式呈现。
本发明还提供了基于在上述组合物的药物组合物,其进一步含有其它惰性组分或药学上可接受辅料,并进一步涉及所述组合物、药物组合物在制备疟疾治疗和/或预防药物中用途;
所述药物组合物可以以剂量单元的形式施用,每个剂量单元含有预定量的活性成分。取决于施用方法、途径,施用对象的患病状况、年龄、体重和健康情况,施用的剂量单元可包含不同剂量的本发明所涉组合。优选剂量单元配方,如日剂量或者份剂量,或是活性成分的相应比例,可由本领域的技术人员根据具体情况应用现有技术或者通过简单实验确定。这类药物组合物可以用药学领域已知的常用方法制备。
所述药物组合物可调整以适应于以任何需要的合适方式施用,例如经口(包括口腔或舌下)、经直肠、经鼻、局部(包括口腔、舌下或透皮)或胃肠外(包括皮下、肌肉内、静脉内或皮内)的方式。此类组合物可用药学领域已知的所有方法,如通过将活性成分与辅料或佐剂进行组合的方法制备。
适用于口服的药物组合物可以以独立的制剂单元施用,包括但不限于:胶囊或片剂;粉剂或颗粒;溶液、水或非水液体混悬液;可食用泡沫或泡沫食品;水包油液体乳或油包水液体乳。因此,以胶囊或片剂为例,活性成分组分可以与可口服、无毒且药学上可接受的惰性辅料,如乙醇、甘油和水等组合。通过将活性化合物粉碎至合适的细小尺寸并与以相同方式粉碎的药用辅料混合制备粉末,所述药用辅料,以可食用碳水化合物为例,可以是淀粉或甘露醇等。调味剂、防腐剂、分散剂和色素同样也可以用作辅料。
胶囊可通过上述方法制备粉末混合物并将其填充在成型的明胶胶囊壳中制备。在填充前,可在粉末混合物中加入诸如高分散硅酸、滑石粉、硬脂酸镁、硬脂酸钙或固态聚乙二醇等助流剂和润滑剂。为提高胶囊服用后药物的利用度,崩解剂或助溶剂,如琼脂、碳酸钙或碳酸钠等,也同样可以加入。此外,如有需要或必需,可在混合物中掺入合适的粘结剂、润滑剂和崩解剂以及色素。适用的粘结剂包括淀粉、明胶、天然糖(如葡萄糖或β-乳糖)、由玉米制得的甜味剂、天然或合成的增稠剂(如阿拉伯胶、黄芪胶或海藻酸钠、羧甲基纤维素、聚乙二醇、蜡类,等等)。制剂中使用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。所述崩解剂包括但不限于淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。
片剂可如下例配制:制备粉末混合物,经湿法或干法制粒,加入润滑剂和崩解剂,然后将其压制成片。粉末混合物的制备具体如下:将经适当方式粉碎的化合物与前文所述的药用辅料混合,并有选择地与粘结剂(例如羧甲基纤维素,海藻酸盐,明胶或聚乙烯吡咯烷酮)、溶出阻滞剂(如石蜡)、吸收促进剂(如四价盐)和/或吸附剂(例如膨润土,高岭土或磷酸二钙)混合。湿法制粒用粘结剂(如糖浆、淀粉糊、阿拉伯胶或纤维素/聚合物材料溶液)润湿粉末混合物,然后挤压过筛制粒。干法制粒直接将粉末混合物过压片机压制成形状不规则的块状物,然后将之粉碎成粒。可通过加入硬脂酸、硬脂酸盐、滑石粉或矿物油润滑制成的颗粒,以防止其粘结在压片模具上。然后将经润滑的颗粒压制成片。也可将活性成分与可自由流动的惰性辅料混合,然后直接压制成片,而无需先进行湿法或干法制粒。片剂可有虫胶密封包衣构成的透明或不透明的包含层,也可有糖或聚合物包衣和蜡打光包衣。可将色素加入到在上述包衣材料中以区分不同的剂量单元。
口服液,例如溶液、糖浆和酏剂,可以以剂量单元的形式制备,以便使给定份量含有预先确定量的化合物。糖浆可通过将化合物溶解于含合适矫味剂的水溶液中制备,酏剂则用非毒性醇溶媒制备。混悬液可通过将化合物分散于非毒性溶媒的方式配制。增溶剂和乳化剂(例如乙氧基化的异硬脂醇类和山梨醇聚氧乙烯醚类)、防腐剂、矫味剂(例如薄荷油、天然的甜味剂、糖精、或其它人造甜味剂等),同样可被加入到制剂中。
如有需要,可将经口施用的剂量单元配方包封于微胶囊中,也可以以释放延长或延迟的方式配制,例如通过将颗粒物包裹或包埋于聚合物、蜡等方式配制。
本发明所涉组合活性成分及其盐、溶剂化物和有生理功能的衍生物,以及其它活性成分也可以脂质体递送系统的方式施用,例如小单层囊泡、大单层囊泡和多层囊泡脂质体。脂质体可以由各种磷脂形成,如胆固醇、硬脂胺或磷脂酰胆碱。
适用于透皮施用的药物组合物可以以独立的贴剂单元施用,以与接受者的皮肤持续、紧密地接触。因此,本发明所涉组合的活性成分可以以药学领域所熟知的膏药形式施用,也可以如Journal of Pharmaceutical Investigation.2021;51(5):503-517.中所概述的,以微针的形式施用。
适用于局部施用的药物组合物可以配制成软膏剂、乳膏剂、混悬剂、洗剂、粉剂、溶液剂、糊剂、凝胶剂、喷雾剂、气雾剂或油剂等。
适用于经直肠施用的药物组合物可以以栓剂或灌肠剂的形式施用。
适用于注射施用的溶液、混悬液可按配方用无菌粉末、颗粒和片剂制备。为达到活性成分的持续和/或可控释放,也可以如Journal of Controlled Release.2017;267(10):57-66.中所概述的方法制备可注射水凝胶用于注射施用。
本发明提供的药物组合物及其制剂可作为人类和兽医学中的药物。
本发明所涉组合的每种活性成分和其它活性成分的治疗有效量或治疗活性剂量取决于多个因素,包括如患者/动物的年龄和体重,需治疗疾病的精准状况及其严重程度,处方制剂的特性和施用方式,最终需由主治医师或兽医确定。
对于含有阿托伐醌(游离酸)和伊维菌素(伊维菌素B1a含量高于85%、伊维菌素B1a和伊维菌素B1b总含量高于90%的混合物)为活性成分的本发明所涉组合,在经口施用情况下,活性成分的成人(假设体重为60kg)日剂量通常如下,阿托伐醌:0.5mg至4000mg,可优选100mg至3000mg,更优选500mg至2000mg或1000mg,每日可分1至4次施用;伊维菌素:6mg至120mg,可优选12mg至80mg,更优选24mg至60mg,每日可分1至4次施用。
对于以阿托伐醌(游离酸)、伊维菌素(伊维菌素B1a含量高于85%、伊维菌素B1a和伊维菌素B1b总含量高于90%的混合物)和青蒿琥酯为活性成分的本发明所涉组合,在经口施用情况下,活性成分的成人(假设体重为60kg)日剂量通常如下,阿托伐醌:0.5mg至4000mg,可优选100mg至3000mg,更优选500mg至2000mg或1000mg,每日可分1至4次施用;伊维菌素:6mg至120mg,可优选12mg至80mg,更优选24mg至60mg,每日可分1至4次施用;青蒿琥酯:2mg至200mg,可优选100mg至200mg,更优选150mg至180mg,每日单次施用。
基于以上,本发明还涉及一种用于治疗和/或预防疟疾的组合包装药品(由各活性组分独立制剂单元组成),首先包含阿托伐醌或其药学活性盐(第一活性组分),其次包含伊维菌素或其药学活性衍生物(第二活性组分)。所涉组合包装药品还可进一步包含青蒿素或其衍生物或药学上可接受的盐作为第三活性组分。
本发明所述的“有效量”指可在组织、系统、动物或人体引起施用者(例如研究者或医师)所寻求或期望的生物或医学反应的药物或药物活性成分的量。
本发明所述的“治疗有效量”指与未被施予该量的相应个体相比,具有以下结果的量:改善治疗,治愈,预防或消除疾病、综合征、病症、主诉、障碍或副反应,亦或减缓疾病、主诉或障碍的进展。“治疗有效量”的表述也包括可有效提升正常生理功能的量。
除另有说明外,此文所用的术语“前药”意指:活性成分的衍生物,其可在生物条件下(体外或体内)可通过水解、氧化亦或其它反应提供活性化合物。前药的范例包括但不限于带有生物可水解官能团的活性成分的衍生物和代谢物,诸如带有生物可水解酰胺、生物可水解酯、生物可水解氨基甲酸酯、生物可水解碳酸酯、生物可水解酰脲和生物可水解磷酸酯的类似物。前药通常可通过本领域已知的方法制备。
本发明具有如下有益技术效果:
减少单一活性组分的施用量,降低潜在毒副反应的风险;协同增效,提高总体施用对疟原虫增殖、配子体形成的抑制效果。
附图说明
图1为阿托伐醌(ATO)、伊维菌素(IVM)单药及其不同摩尔浓度比例组合物对体外培养72小时P.falciparum 3D7、FCC1、NF54和Dd2增殖抑制的量-效曲线。
图2为按不同摩尔浓度比例组合时,在不同抑制水平下(Inhibition),阿托伐醌(ATO)与伊维菌素(IVM)的联合指数(CI,Combination Index)。
图3为阿托伐醌(A)、伊维菌素(B)及二者组合(C)对P.falciparum Dd2体外培养配子体形成的抑制作用;其中,纵坐标为镜检100个视野下的配子体计数,柱状图为每个样品的实际计数值,圆点和竖线为均值标准差;折线为回归模型预测值连线,实线为考虑ATO与IVM相互作用的回归模型预测值连线,虚线为不考虑ATO与IVM相互作用的回归模型预测值连线。
图4为阿托伐醌(ATO)、伊维菌素(IVM)皮下注射单次给药对P.berghei K173感染小鼠寄生虫血症的抑制效果(A,B)及二者以不同剂量比例组合时的药效相互作用结果;其中,数据为8~10只动物的均值±95%置信区间(点和点上竖线)。图A、B纵坐标为相对溶剂对照组平均寄生率的百分比,曲线为3-参数log-logistc模型拟合的量-效曲线。图C中Dato、Divm为组合中所含ATO、IVM的剂量,(EDx)ato、(EDx)ivm为根据量-效曲线估测达到组合对应效应水平(x,也即抑制率)所需单药ATO、IVM的剂量,数据点的形状与颜色代表组合不同的剂量比例,数据点的大小代表其对应到达的抑制率水平。
具体实施方式
下述实施例中所使用的实验方法如无特殊说明,均为常规方法。
下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
下述实施例中所用恶性疟原虫株(P.falciparum):NF54为来自荷兰阿姆斯特丹机场附近的本地恶性疟患者的分离株,3D7通过有限稀释克隆自NF54株,为敏感株;Dd2为老挝抗氯喹恶性疟患者来源分离株在甲氟喹药物压力体外培育获得的多药抗性株,具有氯喹、乙胺嘧啶和甲氟喹抗性;三者皆源自疟疾研究和参考试剂资源中心(Malaria Researchand Reference Reagent Resource Center,MR4)。FCC1为来自1979年恶性疟患者的分离株。以上疟原虫株在本实验室以冷冻保藏和体外培养交替保种。
下述实施例所用鼠疟伯氏疟原虫(P.berghei)K173株为1983年引自英国伦敦卫生与热带医学院医学原虫系,在本实验室以冷冻保藏和血传交替进行保种。
下述实施所用的伊维菌素为伊维菌素B1a和伊维菌素B1b的混合物。其中体外研究所用为Sigmaaldrich公司产品(货号:PHR1380-1G),其伊维菌素B1a的含量为85.8%,伊维菌素B1b的含量为2.5%;体内研究所用为湖北汉威化工有限公司产品(批号:20230310),其含伊维菌素B1a和伊维菌素B1b总含量为95.8%,其中前者占二者总量的99.3%。
下述实施例中的缩略语如下:
ATO,阿托伐醌;CI,联合指数(Combination Index);DMSO,二甲基亚砜;ED,有效剂量;EDTA,乙二胺四乙酸;HEPES,4-(2-羟乙基)哌嗪-乙磺酸;IC,抑制浓度;IVM,伊维菌素;P.berghei,伯氏疟原虫(Plasmodium berghei);P.falciparm恶性疟原虫(Plasmodiumfalciparum);RPMI;Tris,三羟甲基氨基甲烷;LRT,似然比检验(likelihood ratio test)。
以下公开的实施例仅为本发明的部分实施方案,旨在说明本方面。鉴于具体实施时受组合物制剂类型、施用方法与途径、施用对象生物代谢特征等因素的影响,固定比例组分组合最终可达到的疟原虫实际接触组分浓度比例并不一致,且具体实施时组分的优化含量或比例是由本领域的技术人员根据现有技术或者通过简单实验就能够确定的,以下实施例公开的组合物组分浓度比或剂量比不应视为本发明具体实施的限制范围。
实施例1:阿托伐醌(ATO)与伊维菌素(IVM)组合对恶性疟原虫红内期体外增殖的抑制作用及二者的协同增效作用
恶性疟原虫用含有0.5%25mM HEPES、25mM NaHCO3、50mg/L次黄嘌呤、100U青霉素和100μg链霉素的RPMI 1640培养液培养基和人O型红细胞进行体外培养。培养物于含5% O2、5% CO2、90%N2的低氧气氛下,置于37℃进行培养。期间每天更换新鲜培养基,每4~5天补充新鲜人红细胞维持培养。
化合物对恶性疟原虫红内期增殖的抑制作用按Johnson等记载的方法进行测定(Johnson JD,Dennull RA,Gerena L,et al.Assessment and continued validation ofthe malaria SYBR green I-based fluorescence assay for use in malaria drugscreening.Antimicrob Agents Chemother.2007;51(6):1926-33.)。受试化合物用DMSO溶解,并用新鲜培养基稀释配制含梯度浓度ATO、IVM单药或二者不同比例组合物的培养基,按每孔50μL加至黑色96孔微孔板中,每个受试浓度设3个复孔。每个微孔板设有无感染红细胞对照与溶剂对照,以及所有受试浓度单药对照。培养的疟原虫经山梨醇处理同步化后,用新鲜人红细胞稀释调整至起始寄生率为1%,用新鲜培养基调整红细胞压积至4%。按每孔50μL接种于前述已预载药的黑色96孔微孔板中。受试微孔板于同上培养条件下培养72小时后,于每孔加入含浓度SYBR Green I的裂解缓冲液(20mM Tris pH 7.5,5mM EDTA,0.008%(wt/vol)皂素和0.08%(vol/vol)Triton X-100)。混合均匀并室温下孵育2小时,然后用微孔板荧光测定仪测定荧光强度(λex=490nm,λem=520nm),以溶剂对照孔平均值为100%,无感染红细胞对照孔平均值为0%,归一化每孔荧光强度值。取2次以上重复实验数据进行分析,采用4-参数logistic回归模型进行剂量-效应分析(Ritz C,Jensen SM,Gerhard D,et al.Dose-Response Analysis Using R.2019;CRC Press),计算受试单药或组合物的有效抑制浓度(如:IC50、IC60、IC70、IC80、IC90)。组合物抑制浓度表达为组合所含单药摩尔浓度之和。
以基于Loewe相加理论的联合指数法(Chou TC.Theoretical basis,experimental design,and computerized simulation of synergism and antagonismindrug combination studies.Pharmacol Rev.2006;58(3):621-81.)分析ATO与IVM的药效相互作用。组合的联合指数(CI,Combination Index)按以下公式(1)计算:
其中,CIx为组合达到x%抑制时的联合指数;(Dx)1和(Dx)2为药物1和药物2单独使用时达到x%抑制所需的浓度;(D)1和(D)2为组合达到x%抑制时,组合中药物1和药物2的浓度。
当CIx=1时,表明组合中两药相互作用为相加(additive effect);当CIx<1时,表明组合中两药相互作用为协同增效(synergism);当CIx>1时,表明组合中两药相互作用为拮抗(antagonism)。
表1 ATO、IVM单药及不同比例组合对P.falciparum红内期体外培养72小时的抑制作用
*组合的IC50值为所含ATO和IVM摩尔浓度之和。
结果表明ATO、IVM及二者不同比例组合在体外培养72小时的条件下对包括多药抗性的Dd2株在内的4个恶性疟原虫株的红内期增殖都具有显著抑制作用,且其抑制作用呈良好的剂量相关性(图1,数据来自2(不同比例组合物)或4次(ATO和IVM)独立重复实验,每次实验包括三个生物重复(三个复孔)。所有数据以溶剂对照组均值为100%,未感染红细胞对照组均值为0%,进行归一化处理。数据以均值±95%置信区间(点和点上的竖线)表示。其中曲线左右两侧圆点分别为溶剂对照组和未感染红细胞对照组数据。曲线为以4-参数log-logistic模型拟合的量-效曲线。组合对应浓度为所含ATO与IVM浓度之和。)。其IC50都达到了纳摩尔级别,但IVM抑制活性相对较弱,在不同的虫株,其IC50约为ATO的1800多到3200多倍,而ATO与IVM按1:400到1:6400摩尔浓度比组合时,其IC50值在ATO与IVM IC50值之间,且随着组合中IVM所占比例升高而升高(表1)。组合药效相互作用的分析发现,在50%抑制水平以上时,所有受试组合未表现出明显拮抗,其CI值在0.54~1.34,CI值大于1情况主要出现于50%抑制水平之下,在60%抑制水平下,除了在3D7株有两个组合(1:400,1:1600)的CI值大于1,其余虫株测试结果中所有组合CI值皆小于1,而当抑制水平大70%以上时所有组合在所有虫株的CI值都小于1(图2,不同抑制水平下,组合物的CI值由图1所示的量-效曲线模型和公式1计算获得。水平虚线为相加作用(Additive effect)参考线(CI=1)。数据点落于参考线下方提示增效作用,落于参考线上方表示拮抗作用,落于参考线上为相加作用。)。鉴于抑制剂施用时所期望达到的是更高的抑制水平,在高抑制水平下的增效(CI<1)相比于低抑制水平下的相加(CI=1)或弱拮抗(CI略大于1)更具有实际意义。因此,本实施例的结果表明ATO、IVM以摩尔浓度比1:400~1:6400组合时对于恶性疟原虫红内期的增殖抑制无明显的拮抗作用(CI<1.5),且多数情况下可达到协同增效作用。
实施例2:阿托伐醌(ATO)、伊维菌素(IVM)及二者组合对恶性疟原虫配子体形成的抑制作用和二者的协同增效
受试物对恶性疟原虫配子体形成的影响按Guruya等所述方法(Furuya T,Mu J,Hayton K,et al.Disruption of a Plasmodium falciparum gene linked to malesexual development causes early arrest in gametocytogenesis.Proc Natl AcadSci USA.2005,102,16813-16818)进行。P.falciparum Dd2按实施例1中的方法培养,经山梨醇处理同步化后,以起始寄生率0.5%,红细胞压积4%开始培养(D0),D1至D2不做任何处理,于D3开始每天更换新鲜培养基,并使红细胞压积维持在3%,直至D7观察到有滋养体和成熟配子体。离心5分钟收集D7的配子体培养物,用新鲜培养基调整红细胞压积为3%,混匀后分至12孔细胞培养板中,并加入含不同浓度的ATO、IVM或二者组合物的培养基。药物作用下培养24小时后,取每孔样品涂片,进行吉姆萨染色后,后于油镜(物镜)下观察,并计数100个视野中的配子体数,每个样品涂片重复计数3次。计数数据采用泊松回归分析,进行ATO、IVM相互作用的显著性检验。
表2ATO、IVM及二者组合物对P.faciparum Dd2配子体形成的影响
表2为研究结果的总结。当溶剂对照组24小时后样品涂片镜检的每100个视野配子体计数达到了平均50个以上时,ATO、IVM及二者组合皆可显著抑制配子体的形成。其中0.4nM ATO和160nM IVM的组合达到最大抑制(96.7%),强于0.8nM的ATO和800nM的IVM,0.1nM ATO和40nM IVM的组合抑制效果也强于0.2nM的ATO和200nM的IVM(表2)。泊松回归分析表明ATO与IVM之间存在显著相互作用(LRT:),表明ATO与IVM在组合中有显著的增效作用(图3)。
实施例3:阿托伐醌(ATO)与伊维菌素(IVM)组合在伯氏疟原虫感染小鼠模型的药效协同增效作用
在P.berghei K173感染的昆明小鼠评价了ATO、IVM及二者不同比例组合物对动物寄生虫血症的抑制作用。
ATO和IVM用20%DMSO生理盐水(vol/vol)溶解配制成不同浓度溶液,配制的ATO皆为淡黄色色澄清溶液,IVM为均一的白色乳浊液。
昆明小鼠(体重20±2g,雌性)随机分组,每组8只动物,腹腔注射接种个感染红细胞攻虫。攻虫后3小时后通过皮下注射给予不同剂量的ATO、IVM或二者不同剂量比的组合物,安慰剂对照组动物给予等体积的空白溶剂。药后第5天采小鼠尾静脉血涂片,经吉姆萨染色后于油镜(物镜)下观察,计数随机3~5个视野内共1000个以上红细胞中疟原虫感染红细胞数,计算每个动物疟原虫寄生率。取各组动物原虫寄生率均值,用3参数log-logistic回归模型拟合ATO、IVM的剂量-效应曲线,计算半数有效剂量(ED50)。按实施例1中所述方法计算CI值,并用归一化等效线作图法分析药效相互作用(ChouTC.Theoretical basis,experimental design,and computerized simulation ofsynergism and antagonismin drug combination studies.Pharmacol Rev.2006;58(3):621-81.),即用组合中所含ATO、IVM的剂量Dato、Divm分别除以由单药量-效曲线估测达到相同效应水平所需的ATO、IVM剂量(EDx)ato、(EDx)ivm,以其商为X、Y作散点图,并过c(X=0,Y=1)和c(X=1,Y=0)两点作直线为相加作用(additive effect)参考线。组合数据点落于等效线图参考线下方者为协同增效,上方者为拮抗,落于参考线上的为相加作用。
表3ATO、IVM皮下注射单次给药对P.berghei K173感染小鼠寄生虫血症的抑制作用
结果表明ATO和IVM皮下注射单次给药对P.berghei K173感染小鼠寄生虫血症具有剂量相关的抑制作用(图4中A图和B图)。其中,ATO的抑制作用更强,其ED50达到了μg/kg体重级别,而IVM的抑制作用远小于ATO,其ED50为ATO的5000多倍(表3)。以0.016、0.08、0.04、0.02、0.01mg/kg体重剂量ATO与80、40、20、10和5mg/kg体重剂量的IVM两两组合,相同的给药方式下,其对感染动物寄生虫血症的抑制作用如表4所示。CI值与归一化等效线图解分析显示,除了0.002mg/kg ATO与40mg/kg IVM的组合(ATO:IVM=1:20000)CI值略高于1,在等效线图中落于相加线附近,表现为接近相加作用外,其它所有组合CI值皆小于1,且在等效线图中落于相加线下方,表现为协同增效作用(表4和图4中C图)。这表明皮下注射单次给药的情况下,ATO与IVM按剂量比1:625到1:4000组合施用对感染动物寄生虫血症的抑制都具有协同显著的协同增效作用。
表4 ATO、IVM不同剂量组合皮下注射单次给药对P.berghei K173感染小鼠寄生虫血症的抑制作用(n=8)
Claims (10)
1.一种组合物,其特征在于:含有阿托伐醌或其前药或其药学上可接受的盐作为第一活性组分,伊维菌素或其类似物作为第二活性组分。
2.根据权利要求1所述的组合物,其特征在于:所述组合物还含有其它抗疟活性成分,作为第三组分。
3.根据权利要求2所述的组合物,其特征在于:所述第三组分包括但不限于青蒿素、青蒿素衍生物或它们在药学上可接受的盐。
4.根据权利要求3所述的组合物,其特征在于:所述青蒿素衍生物为二氢青蒿素、蒿甲醚、青蒿琥酯及其药学上可接受的盐。
5.根据权利要求1-4中任一项所述的组合物,其特征在于:所述伊维菌素为伊维菌素B1a、伊维菌素B1b或它们的混合物。
6.权利要求1-5中任一项所述组合物用于抑制疟原虫增殖和/或配子体形成的用途;
所述疟原虫包括但不限于恶性疟原虫(Plasmodium falciparum)、伯氏疟原虫(Plasmodium berghei)。
7.根据权利要求6所述的用途,其特征在于:所述组合物的施用方式为不同活性组分同时施用或依次施用。
8.一种药物组合物,其特征在于:包含有权利要求1-5中任一项所述组合物和药学上可接受的辅料。
9.权利要求1-5中任一项所述组合物、权利要求8所述药物组合物在制备疟疾治疗和/或预防的药物中的用途。
10.根据权利要求9所述的用途,其特征在于:所述药物为组合包装药品。
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