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2 (2016) xxx–xxxContents lists available at ScienceDirect
Engineering
ResearchTraditional Chinese Medicine—Review青蒿素——一种从中药中发现的神奇药物ab王继刚a,b,c,#, 徐承超c,#, 王彦钧d,#, 李玉洁a,b, 廖福龙a,b, 姜廷良a,b, 屠呦呦a,b,* Artemisinin Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, Chinac Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapored Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singaporea r t i c l e i n f oArticle history:Received 8 June 2018Revised 1 August 2018Accepted 12 November 2018Available online 18 December 2018摘要青蒿素及其衍生物是治疗疟疾最重要且最具影响力的一类药物。自20 世纪70 年代初发现青蒿素以来，国际上在研究这种非凡的植物化学药物及探明其独特的化学和药理特性方面取得了巨大进展。现今，虽然青蒿素及其衍生物仍然是抗疟的支柱药物，但它们的持续应用和发展也面临许多挑战，包括青蒿素治疗疟疾过程中出现的耐药现象以及青蒿素在其他疾病中的应用。在本文中，我们描述了青蒿素类药物的早期发现、发展过程、应用现状以及未来的发展前景。另外，我们总结了当前的青蒿素机制研究情况并提出了一些看法，同时强调了机制研究对于青蒿素类药物在抗疟以及其他疾病治疗中的重要性。
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关键词青蒿作用机制疟疾抗癌1.引言疟疾自古以来就是一种具有全球影响的衰竭性疾病，至今仍是传播最广泛和最具破坏性的传染病之一[1]。长期以来，疟疾的病因被错误地归咎于“恶劣的空气”，直到19世纪末Charles Louis Alphonse Lave-ran 和Ronald Ross的著作问世，人们才知道疟疾具有传染性和寄生性。他们发现疟原虫属原生动物是导致疟疾的罪魁祸首，按蚊是疟疾感染的主要媒介。这些发现使Laveran和Ross成为了诺贝尔生理学或医学奖的最早获得者[2]。在这些发现问世之后的几十年里，疟疾的治疗取得了突破性进展。20世纪60年代末，中国政府组织了一项旨在寻找抗疟药物的研究，并最终发现了青蒿素。青蒿素（及其衍生物，本文中我们将其称为“青蒿素”）是一种具有独特化学结构的倍半萜烯内酯化合物（图1），来源于紫草属植物黄花蒿（Artemisia annua L.，图2）。自发现以来，它已成为最重要和最有效的抗疟药物[3]。从很多方面看，青蒿素都是一种令人真正着迷的药物。青蒿素传奇的发现过程（从传统药物中筛选和提取的复杂过程）及作为抗疟药物的卓越效力和影响力使它一登上世界舞台就受到了极大的关注[1]。在被发现40多年后，青蒿素仍然是主要抗疟治疗的基础[4]。多年来人们在青蒿素作用机制的研究上做了很多工作[5]。* Corresponding author. E-mail address: yytu@icmm.ac.cn (Y. Tu) 36Author name et al. / Engineering 2(2016) xxx–xxx图1. 青蒿素及其临床应用衍生物。图2. 田间的黄花蒿。除此之外，人们还发现青蒿素具有除抗疟活性以外的其他药理作用，使人们对它的发展充满了期待[6]。鉴于此，我们认为现在应该对这一具有影响力的药物的过去、现在和未来做一个总结。本文回顾了青蒿素的发现和发展历程，总结了当前对于青蒿素在抗疟中的作用机制研究情况，并展望了青蒿素在其他方面的应用前景。本文将对青蒿素做出一个全面的介绍，并基于青蒿素的研究现状发表观点。2.青蒿素的发现首先我们将简要回顾青蒿素发现和发展的非凡历程。中医关于疟疾的记载可以追溯到几千年前，而青蒿作为药材的使用也是如此。首次提到青蒿用于疟疾治疗可以追溯到东晋（公元317—420年）葛洪的《肘后备急方》，随后青蒿和其他技术在疟疾防治中的应用在中国一系列历史医学著作中常有记载，其中包括颇具影响力的李时珍的《本草纲目》（明代，公元1368—1644年）。这些丰富的古代记载对于青蒿素的发现和发展做出了巨大贡献。在第二次世界大战之后的几年里，强力杀虫剂二氯二苯三氯乙烷（DDT）和氯喹（CQ）等新型抗疟药物的研制和部署使疟疾防治工作取得了巨大进展。然而，世界卫生组织（WTO）在20世纪50年代在世界各地抗击和根除疟疾的运动中遇到了与耐药性相关的挑战。DTT耐药载体和耐药寄生虫的出现导致了疟疾的再次爆发，在东南亚和撒哈拉以南非洲地区尤为严重[7]。人们对于新型抗疟药物的需求变得十分迫切。由于越南战争和该地区耐药疟原虫的流行，美国也投入了大量财力研发新型抗疟药物。在此期间，中国政府也开始了抗疟研究工作。中国政府设立了一个名为“523”（以其1967年5月23日启用之日命名）的国家项目，以便在国家级水平上加强抗疟药物的研究[8]。1969年，屠呦呦教授被选为该项目的研究组组长，该研究组致力于在中药中筛选抗疟新药。这项研究是在中国中医科学院中药研究所进行的。屠呦呦和她的同事从大量的中医知识宝库（包括古代文学、民间传说和中医从业者的口头采访）中初步选择了2000多种草药，其中640种被认为是可能有效的中草药，并从其中的200多种草药（包括青蒿/青蒿提取物）中提取了380多种提取物进行测试，大多数结果都不令人满意[1,9]。然而，在1971年，青蒿的提取物引起了他们的特别关注，因为它产生了理想但不稳定的抑制率[1]。这一发现促使他们对文献进行了修正，这可能是发现青蒿素过程中最重要的突破。回到葛洪的《肘后备急方》这一最早使用青蒿治疗疟疾症状的著作，屠呦呦注意到，青蒿的使用方法是使用浸泡青蒿的水，即青蒿的“汁液”。值得注意的是，书中并没有提到中医处方中很常见的药物加热过程。屠
青蒿素 - 一种从中药中发现的神奇药物 - 图文
