CN106109455A - 以5‑氨基乙酰丙酸或其衍生物作为有效成分的抗疟药 - Google Patents
以5‑氨基乙酰丙酸或其衍生物作为有效成分的抗疟药 Download PDFInfo
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- CN106109455A CN106109455A CN201610470997.6A CN201610470997A CN106109455A CN 106109455 A CN106109455 A CN 106109455A CN 201610470997 A CN201610470997 A CN 201610470997A CN 106109455 A CN106109455 A CN 106109455A
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- ala
- malaria
- compound
- antimalarial
- salt
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Abstract
本发明涉及以5‑氨基乙酰丙酸或其衍生物作为有效成分的抗疟药。本发明提供对预防和治疗由疟原虫类引起的传染病有用的抗疟药。本发明使用含有5‑氨基乙酰丙酸(ALA)或其衍生物或者其药理学上容许的盐作为有效成分的疟疾的预防剂和/或治疗剂。
Description
本申请是申请日为2011年5月18日、国际申请号为PCT/JP2011/002770、中国申请号为201180024205.8的中国专利申请的分案申请。
技术领域
本发明涉及对预防和治疗由疟原虫类引起的传染病有用的抗疟药,更详细而言,本发明涉及含有5-氨基乙酰丙酸(ALA)或其衍生物作为有效成分的疟疾的预防剂和治疗剂。
背景技术
疟疾是由疟蚊所传播的疟原虫引起的传染病,并且是以热带、亚热带地区为中心、有史以来人类最害怕的传染病。通过奎宁和氯喹等特效药,曾经暂时观察到感染人数的减少,但从二十世纪五十年代后期开始发现耐药性的原虫,作为再现传染病,目前每年有3~5亿人感染,据称死者有100万人甚至200万人。其他多数传染病可以通过疫苗来治疗、预防,例如天花已被完全消灭,但在疟疾的情况下,由于是由原虫引起的感染并且具有复杂的生命周期,因此,虽然进行了大量研究,但连疫苗开发的线索都未找到,可以说疫苗的开发在本质上是困难的。
虽然对新药剂的开发和耐药性的机制也进行了大量研究,但陆续发现获得了耐药性的原虫,因而唤起了危机感。现有抗疟药一般副作用较强,从而无法在蔓延地带预防性地使用。另外,新药的开发需要庞大的费用,经济问题也较大。
作为治疗方法之一,以往已知光动力治疗(PDT治疗)。PDT治疗是将光敏剂和光照射进行组合的治疗方法。ALA本身不具有光敏性,但在体内代谢后变为光敏物质原卟啉IX(PPIX),因此,在癌症的PDT治疗中使用(例如参考专利文献1~3)。对于使用ALA的PDT疗法,在培养皿上使用疟原虫进行了研究(例如参考非专利文献1)。PDT治疗确实对疟疾显示出效果,但是,为了在通常的室内光的照度下即使微量也显示出效果,需要向培养基中添加2mM的ALA,这对体重60kg的人来说最少需要施用20g的ALA盐酸盐,由于毒性的问题而导致不可能施用。通常人能够耐受的施用量的两倍量为2g,在向培养基中施用相当于2g的0.2mM ALA的情况下,为了观察到充分的杀原虫效果,需要利用410W的强聚光灯进行30分钟的光照射。上述试验是在培养皿上使用透明培养基进行的试验,透光性也高,但实际上,由于疟原虫寄生在血液的红细胞中,因此光照射是不现实的,无法进行后续的研究。
另外,提出了含有ALA和铁化合物作为有效成分的生发剂(例如参考专利文献4)、皮肤粗糙预防剂/改善剂(例如参考专利文献5)。
现有技术文献
专利文献
专利文献1:日本专利第2731032号公报
专利文献2:日本特开2006-124372号公报
专利文献3:日本特表2002-512205号公报
专利文献4:日本专利第3810018号公报
专利文献5:日本专利第3991063号公报
非专利文献
非专利文献1:JID(J.Investigative Dermatology)2004:190,184-191
发明内容
发明所要解决的问题
期望开发出真正有效、副作用少、不易出现耐药性原虫且经济性优良的抗疟药。本发明的课题在于提供含有5-氨基乙酰丙酸(ALA)或其衍生物作为有效成分的、对预防和治疗疟疾有用的抗疟药。
用于解决问题的手段
本发明人对疟原虫的生命周期、以奎宁、氯喹为代表的抗疟药的作用机制、对这些抗疟药的耐受性的研究等进行了详细跟踪,从而发现:疟疾寄生在红细胞中以血红蛋白作为营养;由于消化后的血红蛋白所残留的血红素而受到伤害;为了避免该伤害,疟原虫具有血红素聚合能力而使血红素无害化为疟色素;现有抗疟药的主要作用机制在于抑制该血红素的聚合;耐药性的机理在于促进药剂的排出或使药剂无害化。总而言之,疟疾具有复杂的生命周期且能够逃避免疫,但其最大的弱点是为了以血红蛋白作为营养而不得不靠近血红素,由此受到该血红素的伤害。
本发明人具有如下构思:血红素合成的限速阶段中的ALA或其衍生物可能直接具有抗疟疾作用或者通过其代谢中间体而具有抗疟疾作用。即,想到:作为具有贫血改善效果的化合物而已知的ALA或其衍生物可能直接或通过转变为血红素而直接、间接地伤害原虫,或者由作为其中间体的卟胆原(PBG)、尿卟啉、粪卟啉、原卟啉等中间代谢物直接、间接地伤害原虫,或者通过阻碍现有药物的***等方法对疟原虫的活动发挥抑制性作用。
即使是使用相同的ALA的技术,上述构思与背景技术中介绍的PDT治疗也完全不同,不需要光照射。
对以往作为具有多种健康促进效果的健康食品而已知的ALA确认了抗疟疾的效果,结果,立即抑制了疟疾特有的症状,继而抑制了发热,还抑制了疟原虫的增殖。从反应的快速性来考虑,可知机制与发明人已发现的ALA的免疫失活反应明显不同,并且如已经说明的那样,疟疾通过逃避免疫而寄生,因此,本来就无法用免疫激活来说明。
本发明人进一步对施用方法、与已经获得了耐受性的药剂的组合、施用量等反复进行了各种研究,从而确立了含有ALA作为有效成分的疟疾的治疗剂、预防剂,终于完成了本发明。
即,本发明涉及:
(1)一种疟疾的预防剂和/或治疗剂,其含有5-氨基乙酰丙酸(ALA)或其衍生物或者其药理学上容许的盐作为有效成分。
(2)如上述(1)所述的疟疾的预防剂和/或治疗剂,其特征在于,ALA或其衍生物为由下式(I)表示的化合物,
式中,R1表示氢原子或酰基,R2表示氢原子、直链或支链烷基、环烷基、芳烷基或者芳基。
(3)如上述(2)所述的疟疾的预防剂和/或治疗剂,其特征在于,R1和R2为氢原子。
另外,本发明涉及:
(4)如上述(1)~(3)中任一项所述的疟疾的预防剂和/或治疗剂,其特征在于,通过并用一种或两种以上的含金属化合物来使用。
(5)如上述(4)所述的疟疾的预防剂和/或治疗剂,其特征在于,含金属化合物的金属部分为铁、镁或锌。
另外,本发明涉及:
(6)如上述(1)~(5)中任一项所述的疟疾的预防剂和/或治疗剂,其特征在于,通过并用一种或两种以上的现有抗疟药来使用。
(7)如上述(1)~(6)中任一项所述的疟疾的预防剂和/或治疗剂,其特征在于,以对抗疟药耐受性患者施用的方式使用。
此外,本发明涉及:
用于疟疾的预防和/或治疗的上述(1)~(7)中任一项所述的ALA或其衍生物或者其药理学上容许的盐;
上述(1)~(7)中任一项所述的ALA或其衍生物或者其药理学上容许的盐在疟疾的预防和/或治疗中的应用;
上述(1)~(7)中任一项所述的ALA或其衍生物或者其药理学上容许的盐在制造用于预防和/或治疗疟疾的药物中的应用;
利用含有(1)~(7)中任一项所述的ALA或其衍生物或者其药理学上容许的盐作为有效成分的医药组合物来预防和/或治疗疟疾的方法;
通过施用治疗有效量的(1)~(7)中任一项所述的ALA或其衍生物或者其药理学上容许的盐来预防和/或治疗疟疾的方法。
发明效果
本发明的以ALA作为有效成分的抗疟药具有优良的治疗/预防疟疾的效果。进而,通过与现有抗疟药并用,具有提高药效或者减少副作用强的现有抗疟药的施用量的效果。本发明的抗疟药的机制与现有抗疟药完全不同,着眼于血红素代谢,因此认为不易产生耐药性。另外,通过与已获得了耐受性的现有药并用,能够克服耐受性,从而能够提高现有的廉价且普及的抗疟药的效果。
具体实施方式
本发明中,作为抗疟药使用的由上述式(I)表示的化合物(以下称为“化合物(I)”)的各基团的定义中,烷基可以列举例如:直链或支链的碳原子数1~8的烷基,具体而言,可以列举:甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基、庚基、辛基等。
环烷基可以列举饱和的碳原子数3~8的环烷基或者可存在一部分不饱和键的碳原子数3~8的环烷基,具体而言,可以列举:环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基、1-环己烯基等。
芳烷基的芳基部分与下述芳基具有相同含义,烷基部分与上述烷基具有相同含义,可以列举例如碳原子数7~15的芳烷基,具体而言,可以列举:苄基、苯乙基、苯丙基、苯丁基、二苯甲基、三苯甲基、萘甲基、萘乙基等。
芳基可以列举例如碳原子数6~14的芳基,具体而言,可以列举:苯基、萘基、蒽基、菲基等。
酰基可以列举直链或支链的碳原子数1~8的烷酰基,具体而言,可以列举:甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、新戊酰基、己酰基、辛酰基、苄基羰基等;或者可以列举碳原子数7~14的芳酰基,具体而言,可以列举:苯甲酰基、1-萘甲酰基、2-萘甲酰基等。
本发明的作为抗疟药使用的化合物(I)中,作为ALA衍生物,可以例示ALA的氨基被酰化而得到的化合物和/或羧基被酯化而得到的化合物。优选酰基为甲酰基、乙酰基、丙酰基、丁酰基等的化合物,另外,优选酯基为甲酯、乙酯、丙酯、丁酯、戊酯等的化合物,此外还可以列举:甲酰基与甲酯、乙酰基与甲酯、丙酰基与甲酯、丁酰基与甲酯、甲酰基与乙酯、乙酰基与乙酯、丙酰基与乙酯、丁酰基与乙酯的组合等。
作为化合物(I)的药理学上容许的盐,可以列举药理学上容许的酸加成盐、金属盐、铵盐、有机胺加成盐等。作为酸加成盐,可以列举例如:盐酸盐、氢溴酸盐、氢碘酸盐、磷酸盐、硝酸盐、硫酸盐等各无机酸盐;甲酸盐、乙酸盐、丙酸盐、甲苯磺酸盐、琥珀酸盐、草酸盐、乳酸盐、酒石酸盐、乙醇酸盐、甲磺酸盐、丁酸盐、戊酸盐、柠檬酸盐、富马酸盐、马来酸盐、苹果酸盐等各有机酸加成盐。作为金属盐,可以列举:锂盐、钠盐、钾盐等各碱金属盐;镁盐、钙盐等各碱土金属盐;铝盐、锌盐等各金属盐。作为铵盐,可以列举:铵盐、四甲基铵盐等烷基铵盐等。作为有机胺盐,可以列举:三乙胺盐、哌啶盐、吗啉盐、甲苯胺盐等各盐。
化合物(I)可以通过化学合成、利用微生物进行生产、利用酶进行生产中的任意一种方法来制造。例如,ALA的衍生物中的氨基上的酰基、羧基上的酯基等可以利用化学合成的常规方法通过氨基的酰化或羧基的酯化等来制造。
希望得到化合物(I)的盐时,在化合物(I)以盐的形式得到的情况下,直接进行纯化即可,另外,在化合物(I)以游离的形式得到的情况下,将其溶解或悬浊于适当的有机溶剂中,加入酸或碱后利用通常的方法形成盐即可。
化合物(I)及其药理学上容许的盐有时以与水或各种溶剂的加成物的形式存在,这些加成物也可以作为本发明的抗疟药使用。
能够作为本发明的抗疟药使用的化合物(I)只要是化合物(I)则没有特别限制,可以单独使用化合物(I)中的任意一种,或者可以将两种以上适当组合后使用。化合物(I)中,优选的是ALA、ALA甲酯、ALA乙酯、ALA丙酯、ALA丁酯、ALA戊酯等各种酯类以及它们的盐酸盐、磷酸盐、硫酸盐等,可以例示ALA的盐酸盐、ALA的磷酸盐作为最优选的化合物。
另外,本发明中,也可以与化合物(I)并用地使用含金属化合物。含金属化合物可以在不产生过量症的范围内使用,例如,相对于化合物(I),组合使用0.1~10(重量/重量)倍量、优选0.5~5(重量/重量)倍量、更优选0.8~2(重量/重量)倍量。
作为含金属化合物的金属部分,优选:铁、镁、锌、镍、钒、钴等,其中,优选与卟啉、血红素生物合成相关的金属即铁、镁、锌,这些含金属化合物只要是分子内含有该金属的化合物且不给本发明的效果带来损害则没有特别限制。例如,作为分子内含有铁的化合物,可以列举:柠檬酸亚铁、柠檬酸铁钠、柠檬酸铁铵、焦磷酸铁、血红素铁、右旋糖酐铁、乳酸铁、葡糖酸亚铁、二亚乙三胺五乙酸铁钠、二亚乙三胺五乙酸铁铵、乙二胺四乙酸铁钠、乙二胺五乙酸铁铵、三亚乙四胺铁、二羧甲基谷氨酸铁钠、二羧甲基谷氨酸铵铁铵、乳铁蛋白、转铁蛋白、氯化铁、三氧化二铁、叶绿素铁钠、铁蛋白、富马酸亚铁、焦磷酸亚铁、含糖氧化铁、乙酸铁、草酸铁、琥珀酸亚铁、琥珀酸柠檬酸铁钠、硫酸铁、硫酸甘氨酸铁等,其中,优选柠檬酸亚铁、柠檬酸铁钠。
作为分子内含有镁的化合物,优选:柠檬酸镁、苯甲酸镁、乙酸镁、氧化镁、氯化镁、氢氧化镁、碳酸镁、硫酸镁、硅酸镁、硝酸镁、二亚乙三胺五乙酸镁二铵、乙二胺四乙酸镁二钠、镁原卟啉。
作为分子内含有锌的化合物,优选:氯化锌、氧化锌、硝酸锌、碳酸锌、硫酸锌、二亚乙三胺五乙酸锌二铵、乙二胺四乙酸锌二钠、锌原卟啉、含锌酵母。
上述含金属化合物可以各自单独使用,也可以将两种以上混合使用,可以与化合物(I)同时施用或者分开施用。剂型、施用方法可以与化合物(I)相同,此外也可以不同。
另外,本发明中,也可以与化合物(I)并用地使用现有抗疟药。能够与化合物(I)并用来使用的现有抗疟药没有特别限制,可以列举例如:奎宁、氯喹、甲氟喹、磺胺多辛、乙胺嘧啶、阿托伐醌、氯胍、蒿甲醚、苯芴醇、青蒿琥酯、伯氨喹啉、青蒿素(アルテシミン)等。特别是氯喹、甲氟喹、磺胺多辛、乙胺嘧啶等是过去一直使用的价格低廉的抗疟药,但已知有大量的耐药性原虫,因而通过与化合物(I)并用来消除这些药剂的耐受性的意义重大,可以期待叠加效应,并且根据情况可以期待协同效应。这些抗疟药可以各自单独使用,也可以将两种以上混合使用,可以与化合物(I)同时施用或者分开施用。剂型、施用方法可以与化合物(I)相同,此外也可以不同。
此外,本发明中,可以将化合物(I)单独或与现有抗疟药并用,以对疟疾患者特别是对现有抗疟药获得了耐受性的患者施用的方式使用。
化合物(I)或它们的药理学上容许的盐可以直接单独施用,也可以根据需要添加其他药效成分、营养剂等其他成分,通常优选制成各种医药制剂,该医药制剂可以通过将活性成分与药理学上容许的一种或两种以上的载体混合并利用制剂学的常规方法来制造。作为能够配合在化合物(I)或它们的药理学上容许的盐中的载体,使用适合用于摄取的有机或无机的固态或液态的、通常为惰性的制药学上可容许的载体材料。具体而言,可以例示:微晶纤维素、明胶、乳糖、淀粉、硬脂酸镁、滑石、植物性或动物性脂肪和油、树胶、聚亚烷基二醇等载体。
作为施用途径,可以列举:包括舌下施用在内的经口施用、或吸入施用、包括滴注在内的静脉内施用、利用巴布剂等的经皮施用、栓剂等的非经口施用。
作为施用形式,可以制成注射剂、滴注剂、片剂、胶囊剂、细粒剂、糖浆剂、巴布剂、栓剂等制剂。这些制剂可以通过适当使用溶剂、分散剂、增量剂、赋形剂等并依据常规方法来制造。
例如,注射剂通过添加水、生理盐水、植物油、增溶剂、保存剂等并依据常规方法来制造即可,片剂通过混合例如乳糖、淀粉、硬脂酸镁、羟丙基纤维素、聚乙烯醇、表面活性剂、甘油等各种添加剂并依据常规方法来制造即可,吸入剂通过添加例如乳糖等并依据常规方法来制造即可。需要说明的是,在以水溶液的形式制备这些制剂的情况下,为了防止化合物(I)的分解,需要注意不要使水溶液成为碱性。在成为碱性的情况下,可以通过除去氧来防止有效成分的分解。
化合物(I)或它们的药理学上容许的盐的有效量和施用次数根据施用形式、患者的年龄、体重、症状等而不同,就制剂中含有的化合物(I)的量而言,换算成摩尔数时,化合物(I)的合计以ALA盐酸盐换算通常每一名成人为1mg~3000mg即可,优选为3mg~1000mg,更优选为10mg~700mg,可以在早上施用也可以在晚上施用,无需特别选择施用时间,优选一天施用一次,或者在施用量多时,优选分多次施用。摄取的天数因症状而异,由于疟疾的特征在于间歇性地表现出症状,因此,优选症状缓和后继续摄取3~4天。
以下,通过实施例对本发明更具体地进行说明,但本发明的技术范围不限于这些例示。
实施例1
在医生的指导下对5名罹患疟疾的患者(8岁2名和9岁、10岁、12岁各1名)各自经口施用含有50mg ALA磷酸盐和57.36mg柠檬酸亚铁钠的制剂例1中制造的胶囊一片。在施用后1~2小时,观察到如下改善:全部患者的头痛、眩晕、恶心、倦怠感减轻,无精打采的孩子们开始玩耍。进而,在2~3小时内发热得到改善,6小时后恢复至正常体温。另外,通过摄取前的血液检查,确认到疟原虫。
对全部患者每天一次施用一片该胶囊,在第5天再次检查血液,结果,疟原虫减少但仍然确认到存在。在此期间,包括发热在内的疟疾症状未重现。再施用该胶囊2天,然后中止施用,未出现疟疾的症状。由于症状完全消失,因此视为治愈,未实施治愈后的血液检查。
由本例可知,ALA对治疗疟疾有效。
实施例2
对罹患疟疾并且高热的24岁男性施用制剂例2中制造的含有250mg ALA盐酸盐的胶囊一片,结果,自施用1小时后起,头痛、眩晕、恶心、倦怠感得到改善,自2小时后起发热减轻,1天后症状完全消失。进而,每天一次、每次一片施用该胶囊3天,结果,未观察到症状复发,体温反而显示出比正常体温低约0.5度的值。在第3天的疟原虫检查中,虽然确认到原虫,但并未增加。由此可知,ALA对治疗疟疾有效。
实施例3
使患有疟疾的32岁男性摄取规定量的氯喹,不知是否由于耐受性,未表现出充分的效果,感觉到头痛、眩晕、恶心,发热也在38度左右波动。在摄取氯喹的同时,每天摄取一片与实施例1中使用的胶囊相同的胶囊,结果,约半天时症状得到改善,摄取3天后中止了摄取,但症状未复发。
认为这是由于ALA直接对氯喹耐受性原虫有效地发挥了治疗作用或者通过消除耐受性而有效地发挥了治疗作用。
实施例4
使在疟疾严重污染地区活动的10名受试者每天摄取一片制剂例3中制造的含有25mg ALA磷酸盐和28.68mg柠檬酸亚铁钠的胶囊,在未作防护的状态下活动一个月,在此期间未出现疟疾的感染者。从经验上而言约有一半会感染,因此,认为ALA发挥了预防疟疾感染的作用。
实施例5
向1ml感染率为0.3%的恶性疟原虫3D7培养液中添加氯化铁(II)水溶液以使终浓度达到0.1μM、1μM、10μM、100μM。对照使用添加有灭菌水的培养液,准备各浓度的培养液各3份,使用12孔板。培养48小时后,通过吉姆萨染色测定感染率。另外,对于添加ALA的培养基,添加ALA盐酸盐水溶液以使终浓度达到200μM,并添加氯化铁(II)水溶液以使终浓度达到0.1μM、1μM、10μM、100μM。与上述同样地培养48小时后,通过吉姆萨染色测定感染率。
感染(增殖)率(%)由下式计算:
[(48小时后的感染率-培养开始时的感染率)/(48小时后的对照的感染率-培养开始时的感染率)]×100
需要说明的是,培养开始时的感染率设定为0.3%。
将未添加铁和ALA的区设为100%来表示由培养引起的感染率增加的比例。将结果示于表1中。
[表1]
随机培养的感染率(%)
0 | 0.1μM | 1μM | 10μM | 100μM | |
无ALA | 100 | 98 | 97 | 95 | 82 |
有ALA | 96 | 88 | 86 | 59 | 57 |
由表1可知,ALA具有抑制疟疾感染率的效果,与含金属化合物组合时其效果增强,但单独使用含金属化合物时没有效果。由实施例1~4中示出的对于人的效果可知,疟原虫的感染率降低。
实施例6
根据常规方法,通过5%山梨醇处理,准备同步培养至环状体期的感染率为0.3%的恶性疟原虫3D7培养液,通过与实施例5相同的方法测定感染率。将ALA盐酸盐的终浓度设定为200μM时的结果示于表2中。
[表2]
同步培养(环状体期)的感染率(%)
0 | 0.1μM | 1μM | 10μM | 100μM | |
有ALA | 95 | 69 | 58 | 51 | 5 |
由表2可知,ALA对抑制疟疾感染有效,与含金属化合物组合时其效果显著增强。此外,通过与实施例5比较可知,由ALA以及ALA和含金属化合物带来的感染率抑制效果在环状体期特别显著。只要能够在环状体期抑制疟疾,则无法过渡到滋养体期,因此,如果连续施用,则能够脱离感染,与实施例1~4中的观察结果一致。
实施例7
除了使用2ml感染率为2%的培养液以外,与实施例5同样地制备培养液,向该培养液中添加终浓度为10μM的氯化铁(II)、终浓度为200μM的ALA盐酸盐,并培养8小时。通过吉姆萨染色测定感染率,结果感染率为0.47%。另一方面,未添加任何物质的体系的感染率为3.1%。可知在感染率高的情况下,ALA与含金属化合物的组合对抑制疟疾感染也有效。
实施例8
向与实施例7同样地制备的培养液中添加终浓度为200μM的ALA盐酸盐,培养8小时后,照射15分钟的白色LED。再培养8小时,然后,通过吉姆萨染色测定感染率,结果感染率为1.8%。可知在感染率高的情况下,ALA对抑制疟疾感染也有效。
[制剂例1]
按照由50.0mg ALA磷酸盐、57.36mg柠檬酸亚铁钠、150mgα化淀粉、2.5mg二氧化硅构成的组成,使用2号硬胶囊,通过常规方法进行制备。
[制剂例2]
通过常规方法制备含有250mg ALA盐酸盐的硬胶囊。
[制剂例3]
按照由25.0mg ALA磷酸盐、28.68mg柠檬酸亚铁钠、204mgα化淀粉、2.5mg二氧化硅构成的组成,使用2号硬胶囊,通过常规方法进行制备。
产业上的可利用性
本发明的以ALA作为有效成分的抗疟药能够作为疟疾的治疗剂/预防剂使用。进而,通过与现有抗疟药组合,能够提高药效,或者能够减少副作用强的现有抗疟药的使用量。本发明的抗疟药通过与获得了耐受性的现有药并用,能够克服耐受性,从而能够提高现有的廉价且普及的抗疟药的效果。
Claims (3)
1.下式(I)表示的化合物或其药理学上容许的盐在制造用于预防和/或治疗疟疾的药物中的应用,其中,所述药物仅含有式(I)表示的化合物作为预防和/或治疗疟疾的有效成分并且还含有一种或两种以上的含金属化合物,所述药物在治疗中不需要光照射,通过以5-氨基乙酰丙酸盐酸盐换算计以每一名成人为1~3000mg/天的施用量进行施用而预防和/或治疗疟疾,
式中,R1表示氢原子,R2表示氢原子或直链烷基。
2.如权利要求1所述的应用,其特征在于,R1和R2为氢原子。
3.如权利要求1所述的应用,其特征在于,含金属化合物的金属部分为铁、镁或锌。
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EP3168296B1 (en) * | 2014-07-11 | 2020-09-09 | SBI Pharmaceuticals Co., Ltd. | Agent for improving normal development rate of fertilized eggs |
US10925963B2 (en) * | 2015-06-22 | 2021-02-23 | Washington University | Combination artemisinin and chemiluminescent photodynamic therapy and uses therefor |
CL2016003379A1 (es) * | 2016-12-29 | 2017-08-04 | Univ Santiago Chile | “composición que comprende ácido delta-aminolevulínico (ala) o un derivado del mismo y oxianiones y teluro o sus derivados y su uso para el control de patógenos.” |
CN108635581A (zh) * | 2018-05-23 | 2018-10-12 | 昆药集团股份有限公司 | 一种组合物及其在制备***的药物中的应用 |
JP2022166334A (ja) * | 2019-09-19 | 2022-11-02 | 国立大学法人 東京大学 | 鎌状赤血球症の改善及び/又は予防剤 |
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US5079262A (en) | 1989-07-28 | 1992-01-07 | Queen's University At Kingston | Method of detection and treatment of malignant and non-malignant lesions utilizing 5-aminolevulinic acid |
US5955490A (en) * | 1989-07-28 | 1999-09-21 | Queen's University At Kingston | Photochemotherapeutic method using 5-aminolevulinic acid and other precursors of endogenous porphyrins |
FR2777782B1 (fr) | 1998-04-22 | 2001-05-18 | Alexandre Marti | Solution pour la preparation d'une substance pharmaceutique pour le diagnostic et/ou le traitement de lesions tissulaires |
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WO2006096492A2 (en) * | 2005-03-04 | 2006-09-14 | Dusa Pharmaceuticals, Inc. | Compositions and methods for reducing photosensitivity associated with photodynamic therapy |
EP1878421B1 (en) | 2005-04-28 | 2019-04-03 | SBI Pharmaceuticals Co., Ltd. | External preparation for skin |
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