Treatment of uncomplicated and severe malaria during pregnancy
Umberto D’AlessandroAchille MassougbodjiJoel TärningChristopher PellJayne WebsterJulie GutmanEsperança Sevene
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Artemisinin and its derivatives are important new antimalarial drugs. When Plasmodium falciparum-infected erythrocytes are incubated with [10-3H]dihydroartemisinin, several malaria-specific proteins become labeled. One of these proteins is the P. falciparum translationally controlled tumor protein (TCTP) homolog. In vitro, dihydroartemisinin reacts covalently with recombinant TCTP in the presence of hemin. The association between drug and protein increases with increasing drug concentration, plateauing at approximately 1 drug/TCTP molecule. By Scatchard analysis, there appear to be 2 hemin binding sites on TCTP with dissociation constants of ∼18 μm. When the single cysteine moiety is blocked by pretreatment with iodoacetamide, hemin binding is not affected, whereas drug binding is reduced by two-thirds. Thus, TCTP reacts with artemisinin in situ and in vitro in the presence of hemin and appears to bind to hemin. The function of the malarial TCTP and the role of this reaction in the mechanism of action of artemisinin await elucidation.
Hemin
Dihydroartemisinin
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Artemisinin，首要的抗疟药药的关键成分，每年有大需求。本国的植物，生产 artemisinin 的小数量，作为它的主要来源留下并且因此导致 artemisinin 的短供应。加强的努力被执行了提高 artemisinin 生产。然而，经由在 artemisinin 生合成分支小径的 overexpressing 或下面调整的基因，平淡的新陈代谢的工程策略不是很有效的是需要。腺的能分泌的毛状体， Artemisia annua L 的表面上的 artemisinin 生合成的地点。（ A。annua ) ，是为增加 artemisinin 产量的新目标。一般来说，在 A 的腺的能分泌的毛状体的人口和形态学。annua (AaGSTs ) 断然经常与 artemisinin 内容被相关。AaGSTs 的改进理解将为增加导出植物的 artemisinin 使机会清楚些。在 A 的毛状体的这个评论文章愿望刷新分类。annua 并且关于 AaGSTs 和 artemisinin 提供最近的成就的概述。为了有 AaGSTs，与毛状体形态学被联系的因素和密度愿望的完整的理解，不得不进一步被调查，例如基因， microRNAs 和植物激素。这评论的目的到过(1 ) 更新在 AaGSTs 和 artemisinin 之间的关系的知识，并且(2 ) 建议新大街由利用潜在的 biofactories 增加 artemisinin 产量， AaGSTs。
Artemisia annua
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ABSTRACT Parallel in vitro tests, assessing the inhibition of schizont maturation, were conducted with 31 fresh isolates of Plasmodium falciparum from Thailand, using artemisinin, doxycycline, and combinations of both. The activities of artemisinin and doxycycline are obviously not correlated. Both compounds showed consistent synergism at 50% effective concentration (EC 50 ), EC 90 , and EC 99 levels.
Pharmacodynamics
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Artemisia anuua L 的克隆 S1 的 artemisinin 内容上的发展状态的效果。在一个温室成年在现在的学习被调查。artemisinin 内容在植物的生长的阶段期间逐渐地增加了并且在 89 mg/g 到达了它的高水平当 S1 在一长天(LD ) 是 6 个月旧的时，弄干重量(DW ) 光周期。有短白天(SD ) 的 918 d 的处理光周期导致了到达的 artemisinin 内容并且在高水平(2.0592.289 mg/g DW ) 被维持，双重控制植物和 S1 的植物的在支持花的开始发育、花开始发育的阶段介绍了。artemisinin 内容在植物的不同部分变化了。叶子的 artemisinin 内容比小花和分支的高。在中间的叶子的 artemisinin 内容比底部叶子，然后最高的叶子的高。位于叶子，小花，和分支的表面的头状花序的腺(artemisinin 的存储机关) 的不同密度在植物的这些部分在 artemisinin 内容解释了变化。在 artemisinin 内容和不同机关的表面上的头状花序的腺的密度之间的关联系数是 0.987。为 artemisinin 内容的基因标记用随机的放大多态的 DNA (RAPD ) 和顺序被屏蔽描绘的放大区域(疤) 技术。随机的教材 OPA15 (5-TTCCGAACCC-3 ) 能放大在产出紧张的所有 high-artemisinin 是在场的约 1 000 bp 的一个特定的乐队，但是在三独立复制在所有低产出的紧张不在。这个特定的乐队被克隆，它的顺序被分析。这个 RAPD 标记被变换成一个疤标记获得一个更稳定的标记。
Artemisia annua
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In our ongoing investigation into Artemisia annua for the treatment of malaria, we decided to study the possibility that synergism might enhance the efficacy of artemisinin. Our main objective was to test tea infusions and nonpolar extracts prepared from different A. annua varieties against Plasmodium falciparum in vitro in order to determine if synergism will increase the effectiveness of artemisinin in the samples as compared to pure artemisinin. We found that the IC50 of artemisinin in the tea and nonpolar extracts was not significantly different to the IC50 of pure artemisinin. We could show that the year and country of harvest or storage conditions did not have any influence on the activity and that it narrowly followed the concentration of artemisinin in all the extracts. In conclusion, based on these in vitro results, artemisinin seems to be the only active antiplasmodial compound in A. annua.
Artemisia annua
Artemisia
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Although the biosynthesis of artemisinin is unique to Artemisia annua L., the upstream pathway is ubiquitous among eukaryotes. Therefore, it should be possible to re-establish the downstream pathway for the de novo biosynthesis of artemisinin in eukaryotic microorganisms such as yeast. In the past decade, artemisinin biosynthetic genes have been cloned and introduced into yeast, resulting in the production of several artemisinin precursors including artemisinic acid and dihydroartemisinic acid. However, because of the lack of a suitable cellular environment, these artemisinin precursors failed to be converted into artemisinin. Consequently, A. annua remains the sole source of artemisinin and, therefore, there is a continuing need for research on the genetic improvement of A. annua germlines. Chinese scientists have obtained high-yielding transgenic A. annua plants or varieties using either the opening carbon flux strategy or the closing carbon flux strategy. These studies have shed light on the accelerated and sustainable production of artemisinin. In addition, the rate-limiting steps of artemisinin biosynthesis, particularly the final reaction mechanism, have been identified and characterized. This information is important to simulate the cellular environment in transgenic systems, to enable the successful production and accumulation of artemisinin. Together, these studies have paved the way towards a solution to the problem of limited artemisinin supply. Finally, we discuss the implications of patents for microorganisms that produce artemisinin precursors, and the ways in which China can avoid patent infringements.
Artemisia annua
Metabolic Engineering
Synthetic Biology
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Artemisia annua
Sesquiterpene lactone
Metabolic Engineering
Antimalarial Agent
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Evaluation of: Batty KT, Salman S, Moore BR et al. Artemisinin–naphthoquine combination therapy for uncomplicated pediatric malaria: a pharmacokinetic study. Antimicrob. Agents Chemother. 56(5), 2472–2484 (2012).Artemisinin-based combination therapies (ACTs) have been adopted as the first line of treatment against malaria in nearly all malaria-endemic countries, mainly as a result of Plasmodium falciparum infection, as this species of malaria parasite has developed resistance to most of the available non-artemisinin antimalarial drugs. Artemisinin–naphthoquine (ART–NQ, also named as ARCO™; Kunming Pharmaceuticals, Kunming, China) is one of the several currently available ACTs that show a promising approach to dealing with drug-resistant malaria rather than monotherapies. Unlike other ACTs, ART–NQ requires either a single-dose treatment or a two-dose treatment within 24 h against uncomplicated P. falciparum malaria; however, this was mainly validated in adults rather than children. Batty et al. performed the first pharmacokinetic study of ART–NQ combination therapy for uncomplicated pediatric malaria, and the authors' results are described and discussed below.
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