青蒿素

Selective cancer cell cytotoxicity from exposure to dihydroartemisinin and holotransferrin

Lai, H; Singh, NP

Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: A prospective study

Nosten, F; van Vugt, M; Price, R; et al.

Amodiaquine-artesunate versus amodiaquine for uncomplicated Plasmodium falciparum malaria in African children: A randomised, multicentre trial

Adjuik, M; Agnamey, P; Babiker, A; et al.

Identification of intermediates and enzymes involved in the early steps of artemisinin biosynthesis in Artemisia annua

Bertea, CM; Freije, JR; van der Woude, H; et al.

The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine

Tu, YY

Total synthesis of Qinghaosu

Schmid, G; Hofheinz, W

High-level semi-synthetic production of the potent antimalarial artemisinin

Paddon, CJ; Westfall, PJ; Pitera, DJ

Ri質粒轉化的青蒿發根培養及青蒿素的生物合成

蔡國琴，李國珍，葉和春，等

熱點追蹤

青蒿素

·編者按·

青蒿素（artemisinin，qinghaosu）及其衍生物是臨床上治療瘧疾的一線藥物，也是現今所有藥物中起效最快的抗惡性瘧原蟲瘧疾藥。青蒿素提取自常用中藥一年生菊科植物黃花蒿，1972年，中國科學家屠呦呦領導的課題組首次從這種植物中分離得到抗瘧疾的有效單體，她本人也因此獲得2011年拉斯克-德貝基臨床醫學獎和2015年諾貝爾生理學或醫學獎。

青蒿素及其衍生物（主要包括雙氫青蒿素、蒿甲醚、蒿乙醚和青蒿琥酯）結構中具有一個包括過氧基團在內的1,2,4-三噁烷結構單元，一般認為這種結構與青蒿素的抗瘧活性有關。臨床證明，使用基于青蒿素類抗瘧藥的聯合治療方案（artemisinin-based combination therapies，ACTs）治療瘧疾能夠取得很好的效果。因而，ACTs被世界衛生組織推薦為治療瘧疾的一線藥物。近年來，研究發現青蒿素類藥物除抗瘧作用外，還有多種其他的藥理作用，包括抗多種寄生蟲（血吸蟲和弓形蟲等）、抗細菌膿毒癥、放療增敏、抗菌增敏、抗腫瘤、抗心律失常等作用，在這些方面具有潛在的開發價值。

藥用青蒿素主要是從中藥青蒿的原植物黃花蒿的葉和花蕾中分離獲得，但是含量較少，需要采集大量自然資源，加工環節也比較多，導致青蒿素的供需矛盾。因而，青蒿素的來源問題成為該領域研究重點之一。對該問題的研究主要包括青蒿素的化學合成方法和生物合成方法。其中，青蒿素化學合成有全合成和半合成2種，全合成的原料主要是香茅醛（citronellal）、檸檬烯（isolimonene）、薄荷酮（pulegone）、β-蒎烯（β-pinene）、異胡薄荷醇（isopulegol）等，半合成原料主要是青蒿酸。青蒿素的生物合成途徑尚未完全清楚，其合成相關基因包括紫穗槐-4,11-二烯氧化酶基因、細胞色素P450氧化還原酶基因、青蒿醛雙鍵還原酶和醛脫氫酶基因。2013年Keasling J D以及Lévesque F等研究者報道了采用合成生物學方法，利用基因工程酵母成功生產青蒿酸，并進一步高效半合成得到青蒿素的研究結果。這一成果有望進一步實現產業化應用。目前青蒿素的現實來源主要還是從中藥青蒿的原植物中提取。

本專題得到了曾慶平教授（廣州中醫藥大學）、王滿元副教授（首都醫科大學）的大力支持。

·熱點數據排行·

截至2015年10月30日，中國知網（CNKI）和Web of Science（WOS）的數據報告顯示，以“青蒿素（artemisinin）”為主題檢索到的期刊文獻分別為3026為與5659條，本專題將相關數據按照：研究機構發文數、作者發文數、期刊發文數、被引用頻次進行排行，結果如下。

研究機構發文數量排名（CNKI）

研究機構發文數量排名（WOS）

作者發文數量排名（CNKI）

作者發文數量排名（WOS）

期刊發文數量排名（CNKI）

期刊發文數量排名（WOS）

根據中國知網（CNKI）數據報告，以“青蒿素（artemisinin）”為主題檢索到的高被引論文排行結果如下。

國內數據庫高被引論文排行

根據Web of Science統計數據，以“青蒿素（artemisinin）”為詞條檢索到的高被引論文排行結果如下。

國外數據庫高被引論文排行

·經典文獻推薦·

基于Web of Science檢索結果，利用Histcite軟件選取LCS（Local Citation Score，本地引用次數）TOP 50文獻作為節點進行分析，結合專家意見，得到本領域推薦的經典文獻如下。

經典文獻

來源出版物：Antimicrobial Agents and Chemotherapy, 1993, 37(5): 1108-1114

Selective cancer cell cytotoxicity from exposure to dihydroartemisinin and holotransferrin

Lai, H; Singh, NP

Abstract: Rapid cell death, as evidenced by a decrease in cell counts, was observed when molt-4-lymphoblastoid cells, a human leukemia cell line, were exposed to holotransferrin (12 micro M) and dihydroartemisinin (1-200 micro M).Incubation with either compound alone was significantly less effective.Significantly less cell death was observed when normal human lymphocytes were exposed to a combination of these 2 drugs.Probit analysis of dose-response functions shows that the drug combination is approximately 100 times more effective on molt-4 cells than lymphocytes (LD(50)s for molt-4 and lymphocytes were 2.59 micro M and 230 micro M, respectively).This drug combination may provide a novel approach for cancer treatment.

Keywords: Molt-4-lymphoblastoid cells; lymphocytes; holotransferrin; dihydroartemisinin

來源出版物：Cancer letters, 1995, 91(1): 41-46

Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: A prospective study

Nosten, F; van Vugt, M; Price, R; et al.

Abstract: Background: Worsening drug resistance in Plasmodium falciparum malaria is a major threat to health in tropical countries.We did a prospective study of malaria incidence and treatment in an area of highly multidrug-resistant P falciparum malaria.Methods: We assessed incidence of P falciparum malaria and the in-vivo responses to mefloquine treatment over 13 years in two large camps for displaced Karen people on the northwest border of Thailand.During this time, the standard mefloquine dose was first increased, and then combined artesunate and mefloquine was introduced as first-line treatment for uncomplicated P falciparum malaria.Findings: Early detection and treatment controlled P falciparum malaria initially while mefloquine was effective (cure rate with mefloquine [15 mg/kg] and sulphadoxine-pyrimethamine in 1985, 98% [95% CI 97-100]), but as mefloquine resistance developed, the cure rate fell (71% [67-77] in 1990).A similar pattern was seen for high-dose (25 mg/kg) mefloquine monotherapy from 1990-94.Since the general deployment of the artesunate-mefloquine combination in 1994, the cure rate increased again to almost 100% from 1998 onwards, and there has been a sustained decline in the incidence of P falciparum malaria in the study area.In-vitro susceptibility of P falciparum to mefloquine has improved significantly (P=0.003).Interpretation: In this area of low malaria transmission, early diagnosis and treatment with combined artesunate and mefloquine has reduced the incidence of P falciparum malaria and halted the progression of mefloquine resistance.Werecommend that antimalarial drugs should be combined with artemisinin or a derivative to protect them against resistance.

Keywords: Burmese border; monoclonal-antibodies; elisa development; bed nets; sporozoites; epidemiology; prevention; pregnancy; area

來源出版物：The Lancet, 2000, 356(9226): 297-302

Amodiaquine-artesunate versus amodiaquine for uncomplicated Plasmodium falciparum malaria in African children: A randomised, multicentre trial

Adjuik, M; Agnamey, P; Babiker, A; et al.

Abstract: Background: Increasing drug resistance limits the choice of efficacious chemotherapy against Plasmodium falciparum malaria in Africa.Amodiaquine still retains efficacy against P falciparum in many African countries.We assessed the safety, treatment efficacy, and effect on gametocyte carriage of adding artesunate to amodiaquine in three randomised trials in Kenya, Senegal, and Gabon.Methods: We enrolled 941 children (400 in Kenya, 321 in Senegal, and 220 in Gabon) who were 10 years or older and who had uncomplicated P falciparum malaria.Patients were randomly assigned amodiaquine (10 mg/kg per day for 3 days) plus artesunate (4 mg/kg per day for 3 days) or amodiaquine (as above) and placebo (for 3 days).The primary endpoints were parasitological cure rates at days 14 and 28.Analysis was by intention to treat and by an evaluability method.Findings: Both regimens were well tolerated.Six patients in the amodiaquine-artesunate group and five in the amodiaquine group developed early, drug-induced vomiting, necessitating alternative treatment.By intention-to-treat analysis, the day-14 cure rates for amodiaquine-artesunate versus amodiaquine were: 175/192 (91%) versus 140/188 (74%) in Kenya (Delta=16.7% [95% CI 9.3-24.1], P<0.0001), 148/160 (93%) versus 147/157 (94%) in Senegal (-1.1% [-6.7 to 4.5], P=0.7), and 92/94 (98%) versus 86/96 (90%) in Gabon (8.3% [1.5-15.1], P=0.02).The corresponding rates for day 28 were: 123/180 (68%) versus 75/183 (41%) in Kenya (27.3% [17.5-37.2], P<0.0001), 130/159 (82%) versus 123/156 (79%) in Senegal (2.9% [-5.9 to 11.7], P=0.5), and 80/94 (85%) versus 70/98 (71%) in Gabon (13.7% [2.2-25.2], P=0.02).Similar rates were obtained by evaluability analysis.Interpretation: The combination of artesunate and amodiaquine improved treatment efficacy in Gabon and Kenya, and was equivalent in Senegal.Amodiaquine-artesunate is a potential combination for use in Africa.Further investigations to assess the potential effect on the evolution of drug resistance, disease transmission, and safety of amodiaquine-artesunate are warranted.

Keywords: pyrimethamine-sulfadoxine; antimalarial drug; double-blind; efficacy; chloroquine; resistance; artemether; benflumetol; combination; CGP-56697

來源出版物：The Lancet, 2002, 359(9315): 1365-1372

Identification of intermediates and enzymes involved in the early steps of artemisinin biosynthesis in Artemisia annua

Bertea, CM; Freije, JR; van der Woude, H; et al.

Abstract: An important group of antimalarial drugs consists of the endoperoxide sesquiterpene lactone artemisinin and its derivatives.Only little is known about the biosynthesis of artemisinin in Artemisia annua L., particularly about the early enzymatic steps between amorpha-4,11-diene and dihydroartemisinic acid.Analyses of the terpenoids from A.annua leaves and gland secretory cells revealed the presence of the oxygenated amorpha-4,11-diene derivatives artemisinic alcohol, dihydroartemisinic alcohol, artemisinic aldehyde, dihydroartemisinic aldehyde and dihydroartemisinic acid.We also demonstrated the presence of a diene synthase and the -so far unknown -amorpha-4,11-diene hydroxylase as well as artemisinic alcohol and dihydroartemisinic aldehyde dehydrogenase activities in both leaves and glandular trichomes.From these results, we hypothesise that the early steps in artemisinin biosynthesis involve amorpha-4,11-diene hydroxylation to artemisinic alcohol, followed by oxidation to artemisinic aldehyde, reduction of the C11-C13 double bond to dihydroartemisinic aldehyde and oxidation to dihydroartemisinic acid.

Keywords: artemisia annua; asteraceae; artemisinin; glandular trichomes; biosynthetic pathway; sesquiterpenoids

來源出版物：Planta medica, 2005, 71(1): 40-47

The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine

Tu, YY

Abstract: Joseph Goldstein has written in this journal that creation (through invention) and revelation (through discovery) are two different routes to advancement in the biomedical sciences.In my work as a phytochemist, particularly during the period from the late 1960s to the 1980s, I have been fortunate enough to travel both routes.

來源出版物：Nature Medicine, 2011, 17(10):1217-1220

Total synthesis of Qinghaosu

Schmid, G; Hofheinz, W

Abstract: Since ancient time Artemisia annua also called qinghao has been used to treat fever in china.The effective constituent waslsolate by chinese scientist in 1972 named qinghaosu also known as Artemisinin.It can be used to treat drug-resistant malaria which causes millions death every year in developing countries of Asia Africa and America.

來源出版物：Journal of the American Chemical Society, 1983, 105(3): 624-625

High-level semi-synthetic production of the potent antimalarial artemisinin

Paddon, CJ; Westfall, PJ; Pitera, DJ

Abstract: In 2010 there were more than 200 million cases of malaria, and at least 655000 deaths.The World Health Organization has recommended artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum.Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua.However, the supply of plant-derived artemisinin is unstable, resulting in shortages and price fluctuations, complicating production planning by ACT manufacturers.A stable source of affordable artemisinin is required.Here we use synthetic biology to develop strains of Saccharomyces cerevisiae (baker’s yeast) for high-yielding biological production of artemisinic acid, a precursor of artemisinin.Previous attempts to produce commercially relevant concentrations of artemisinic acid were unsuccessful, allowing production of only 1.6 grams per litre of artemisinic acid.Here we demonstrate the complete biosynthetic pathway, including the discovery of a plant dehydrogenase and a second cytochrome that provide an efficient biosynthetic route to artemisinic acid, with fermentation titres of 25 grams per litre of artemisinic acid.Furthermore, we have developed a practical, efficient and scalable chemical process for the conversion of artemisinic acid to artemisinin using a chemical source of singlet oxygen, thus avoiding the need for specialized photochemical equipment.The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic artemisinin to stabilize the supply of artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs.Because all intellectual property rights have been provided free of charge, this technology has the potential to increase provision of first-line antimalarial treatments to the developing world at a reduced average annual price.

來源出版物：Nature, 2013, 496(7446): 528-532

·高被引論文摘要·

被引頻次：132

Ri質粒轉化的青蒿發根培養及青蒿素的生物合成

蔡國琴，李國珍，葉和春，等

用發根農桿菌（Agrobacterium rhizogenes）轉化藥用植物青蒿（Artemisia annua L.）并建立了發根體外培養系統。Southern雜交、NPTⅡ酶的檢測證明Ri質粒的T-DNA轉移并整合到植物的核基因組上。在發根培養系統中，檢測了青蒿的重要次生代謝物—青蒿素的含量，檢測了不同理化因子對發根生長及青蒿素含量的影響。結果表明：光照（日光燈，12 h光周期，2000 Lx）有利于次生產物青蒿素的積累。培養基的pH值為5.4。蔗糖濃度為3%不僅促進發根的生長，而且促進青蒿素的積累。低濃度親乙酸（NAA）對發根生長具有促進作用，但抑制青蒿素的合成。赤霉素GA3對發根的生長及次生產物的合成都具有促進作用，其最適濃度為4.8 mg/L。

青蒿；Ri質粒；發根；青蒿素

來源出版物：生物工程學報, 1995, 11(4): 315-320

被引頻次：98

青蒿素（Arteannuin）的結構和反應

劉靜明，倪慕云，樊菊芬，等

摘要：青蒿素是一個含過氧基團的新型倍半萜化合物，系從黃花蒿中分得。它的結構是由紅外光譜、核磁共振譜、質譜和化學反應以及X-射線衍射等方法確定的。它的絕對構型是根據與化合物（6）構型聯系以及利用氧原子的反常散射測定的。

關鍵詞：青蒿素；Arteannuin；倍半萜化合物；乙醚提??；紅外光譜；過氧基；青篙素；核磁共振譜；絕對構型；反常散射

來源出版物：化學學報, 1979, 37(2): 129-143

被引頻次：87

微波輔助提取青蒿素的研究

韓偉，郝金玉，薛伯勇，等

摘要：目的：運用新型分離方法微波輔助提取法（MAE）來提取黃花蒿中的青蒿素。方法：分別選用乙醇、三氯甲烷、環己烷、正己烷、30℃～60℃石油醚、60℃～90℃石油醚、120號溶劑油、6號抽提溶劑油作為萃取介質，在間歇微波輔助提取裝置中，進行微波輔助提取實驗。結果：從微波輻射時間、溶劑比、物料粉碎度等工藝條件對青蒿素得率的影響。評價最佳溶劑是6號抽提溶劑油。結論：微波輔助提取法適合于提取黃花蒿中的青蒿素。

關鍵詞：微波輔助提??；微波萃??；青蒿素；黃花蒿

來源出版物：中成藥, 2002, 24(2): 83-86

被引頻次：78

青蒿素對人白血病細胞株和原代細胞的影響

周晉，孟然，李麗敏，等

摘要：青蒿素是一種低毒、有效的抗瘧藥，最近發現其有抑制實體瘤細胞增殖的作用。我們研究了青蒿素對人白血病細胞株和原代細胞的影響及可能機制，以期為其抗白血病新用途提供實驗證據。

關鍵詞：人白血病細胞株；青蒿素；原代細胞；細胞內鈣；細胞超微結構；細胞凋亡；瘤細胞增殖；胞膜破壞；血液病研究所；實驗分組

來源出版物：中華內科雜志, 2004, 42(10): 713-714

被引頻次：78

青蒿素誘導K562細胞凋亡研究

董海鷹，王知非，宋維華，等

摘要：目的：研究青蒿素對體外培養的K562細胞的凋亡誘導作用及機制。方法：MTT法測定藥物對K562細胞生長的抑制作用；透射電鏡觀察藥物對K562細胞形態學的影響；流式細胞儀檢測經藥物作用后的細胞凋亡率；用Rhodamine（Rh123）色法檢測細胞線粒體跨膜電位（Δψm）的變化。結果：青蒿素對 K562細胞生長有明顯的抑制作用，細胞經藥物作用48小時后的 IC50為26.5 μmol/L；電鏡觀察細胞有典型的凋亡形態特征；細胞凋亡率在一定范圍內與藥物濃度正相關。給藥后跨膜電位明顯下降。結論：青蒿素可抑制K562細胞的生長，誘導K562細胞跨膜電位下降而導致細胞凋亡。

關鍵詞：青蒿素；細胞；MTT法；凋亡

來源出版物：中國腫瘤, 2003, 12(8): 473-475

被引頻次：73

冬蟲夏草和青蒿素抑制狼瘡性腎炎復發的研究

盧嵐

摘要：目的：觀察冬蟲夏草（簡稱蟲草）和青蒿素抑制狼瘡性腎炎復發的作用。方法：61例經用激素及環磷酰胺沖擊治療已無狼瘡活動的狼瘡性腎炎患者，隨機分為兩組，治療組（31例）予蟲草粉每日3～4 g，分3次空腹口服；青蒿素粉每日0.6 g，分3次餐后口服，連續服用3年。對照組（30例）口服雷公藤多甙片和（或）保腎康片等藥物治療。兩組均連續觀察5年，監測血肌酐、肌酐清除率、抗核抗體等實驗室有關指標及有否狼瘡活動的臨床表現。結果：治療組顯效26例（83.9%），有效4例（12.9%），無效1例（3.2%）；對照組顯效15例（50.0%），有效8例（26.7%），無效7例（23.3%），兩組顯效率比較差異有顯著性（P<0.01)。治療組補體C3持續穩定在（1.21 ± 0.20）g/L正常水平，肌酐清除率治療前后比較差異無顯著性，與對照組比較差異有顯著性；治療組同時減少了藥物本身的不良反應。結論：冬蟲夏草和青蒿素可以抑制狼瘡腎炎的復發，保護腎功能。

關鍵詞：冬蟲夏草；青蒿素；狼瘡性腎炎；復發

來源出版物：中國中西醫結合雜志, 2002, 22(3): 169-171

被引頻次：71

青蒿素和青蒿琥酯對人乳腺癌MCF-7細胞的體外抑制作用比較研究

林芳，錢之玉，薛紅衛，等

摘要：目的：對比研究青蒿素及其衍生物青蒿琥酯對人乳腺癌MCF-7細胞增殖的影響并探討其作用機制。方法采用體外培養的人乳腺癌MCF-7細胞株，利用SRB法測定青蒿素和青蒿琥酯對MCF-7細胞增殖的影響，FCM法測定細胞周期的變化，亞G1期含量測定和DAPI熒光染色法觀察細胞凋亡。結果：10 μmol/L青蒿素和1 μmol/L青蒿琥酯能明顯改變MCF-7細胞的細胞周期，使S期細胞顯著減少，G0+G1期細胞明顯增加。青蒿素對 MCF-7細胞增殖僅有微弱抑制作用，但其衍生物青蒿琥酯卻有顯著的抑制作用，IC50為0.31 μmol/L。同樣，1 μmol/L青蒿琥酯引起MCF-7細胞的凋亡和直接的細胞毒作用明顯強于10 μmol/L青蒿素的作用。結論：體外研究表明，對腫瘤細胞增殖的抑制青蒿琥酯比青蒿素作用強。

關鍵詞：青蒿素；青蒿琥酯；MCF-7細胞

來源出版物：中草藥, 2003, 34(4): 347-349

被引頻次：71

青蒿素抗心律失常作用及機制

李寶馨，楊寶峰，李玉榮

摘要：目的：觀察青蒿素抗心律失常作用，并探討其作用機制。方法：采用冠脈結扎，氯化鈣，氯仿所致心律失常模型進行青蒿素的抗心律失常作用研究。應用膜片鉗技術研究藥物對內向整流鉀電流的作用。結果：青蒿素能明顯對抗結扎冠脈引起的心律失常，對氯化鈣、氯仿引起的心律失常，可使其發生時間明顯延長，室顫明顯減少。膜片鉗實驗表明，該藥可劑量依賴性的明顯抑制內向整流鉀電流。結論：該藥是一有效的抗心律失常藥，其作用機制與其抑制內向整流鉀電流有關。

關鍵詞：青蒿素；心律失常；內向整流鉀電流

來源出版物：中國藥理學通報, 1999, 15(5): 449-452

被引頻次：70

二氫青蒿素對人乳腺癌MCF-7細胞的體外抑制作用

林芳，錢之玉，丁健，等

摘要：目的：研究二氫青蒿素（青蒿素生物合成中的可能前體）對腫瘤細胞增殖的影響和機制。方法：采用體外培養的人乳腺癌MCF-7細胞株，利用SRB法測定青蒿素和青蒿琥酯對MCF-7細胞增殖的影響，用流式細胞檢定法（FCM）測定細胞周期的變化，用亞G1期含量測定法和DAPI熒光染色法觀察細胞凋亡。結果：二氫青蒿素能顯著抑制MCF-7細胞的增殖，IC50為0.26 μmol·L-1；二氫青蒿素作用后細胞周期發生明顯變化，細胞被阻滯在G0+G1期，S期細胞顯著減少。二氫青蒿素作用細胞24 h后可輕微誘導MCF-7細胞凋亡。結論：二氫青蒿素能強烈抑制MCF-7細胞增殖，將細胞阻滯于G0+G1期。

關鍵詞：二氫青蒿素；人乳腺癌細胞MCF-7；細胞周期

來源出版物：中國新藥雜志, 2002, 11(12): 934-936

被引頻次：69

青蒿素類藥物的研究現狀

李國棟，周全，趙長文，等

摘要：目的：從幾個方面介紹青蒿素類藥物的研究現狀，為青蒿素類藥物的研究提供參考。方法：依據國內外文獻進行綜述，包括人工栽培青蒿提取有效成分和人工合成方法兩種制備青蒿素的途徑以及青蒿素類藥物活性成分測定方法、抗瘧作用機制、藥動學、藥效學和毒理學的研究進展及臨床應用情況。結果：青蒿素類藥物是有發展前途的藥物，它們的各方面研究已取得一定的進展。結論：青蒿素類藥物為人類對瘧疾的斗爭注入了新的活力。

關鍵詞：青蒿素；衍生物；瘧疾

來源出版物：中國藥學雜志, 1998, 33(7): 385-389

被引頻次：68

超聲波用于強化石油醚提取青蒿素

趙兵，王玉春，吳江，等

摘要：研究了用超聲波強化石油醚提取青蒿素的工藝過程。與常規石油醚提取比較，用超聲波不僅可以大大縮短提取時間，減少提取產物中雜質含量，而且還可以降低溶劑消耗。

關鍵詞：青蒿素；提??；超聲波

來源出版物：化工冶金, 2000, 21(3): 310-313

被引頻次：58

青蒿素類藥物的藥理作用研究進展

譚濤，秦宗會，譚蓉

摘要：青蒿素是從植物黃花蒿中提取的抗瘧疾活性成分,在臨床上廣泛用于治療瘧疾。由于青蒿素類藥物還具有抗瘧疾、抗孕、抗纖維化、抗血吸蟲、抗弓形蟲、抗心律失常和腫瘤細胞毒性等藥理作用，且具有安全、高效、無耐藥性等優點，備受國內外學者關注。筆者對近年來青蒿素類藥物的其他主要藥理學作用研究的現狀進行了綜述。

關鍵詞：青蒿素；藥理作用；進展

來源出版物：中國藥業, 2009, 18(3): 63-64

被引頻次：57

黃花蒿中青蒿素的微波輔助提取

郝金玉，韓偉，施超歐，等

摘要：采用微波輔助提取法提取黃花蒿中的青蒿素。對提取溶劑乙醇、三氯甲烷、環己烷、正己烷、石油醚（30～60°C和 60～90℃兩種）、120號溶劑油和6號抽提溶劑油進行了比較，考察了溶劑的介電常數對青蒿素得率的影響。并將微波輔助提取法同索氏提取、超臨界CO2提取以及加熱攪拌提取法進行了比較。

關鍵詞：微波輔助提??；青蒿素；黃花蒿；超臨界CO2提取

來源出版物：中國醫藥工業雜志, 2002, 33(8): 385-387

被引頻次：55

青蒿素局部治療增殖性瘢痕臨床觀測

賀光照，黃崇本，張代錄，等

摘要：青蒿素局部治療60例增殖性瘢痕。定量測定用藥前和用藥后1月、2月、3月瘢痕的硬度、溫度和厚度。以便客觀評價青蒿素的藥物療效。結果表明：瘢痕厚度在治療后顯著低于治療前（P<0.01）；瘢痕硬度在治療后逐漸降低，依次為3月<2月<1月（P<0.01）；瘢痕硬度在治療后3月顯著低于治療前（P<0.05）。瘢痕溫度改變在治療前后無統計學顯著意義（P>0.05）。根據療效評價標準，青蒿素治療50例病人總有效率為88%，其中顯效率為46%，無效率為12%。

關鍵詞：青蒿素；增殖性瘢痕

來源出版物：重慶醫科大學學報, 1998, 23(3): 260-262

被引頻次：55

青蒿素研究進展

李偉，石崇榮

摘要：青蒿素（Artemisinin）是我國藥學工作者1971年從菊科植物黃花蒿Artemisia annua L.葉中提取分離到的一種具有過氧橋的倍半萜內酯類化合物。在青蒿素的基礎上又開發出了多種衍生物雙氫青蒿素（Dihydro artemisinin）、青蒿琥酯（Artesunate）、蒿甲醚（Artemether）、蒿乙醚（Arteether），均有抗瘧、抗孕、抗纖維化、抗血吸蟲、抗弓形蟲、抗心律失常和腫瘤細胞毒性等作用。青蒿素類藥作用廣泛，其作用機制、特點、應用研究仍處于初級階段, 有待進一步開發?，F就青蒿素近年在上述各方面的研究進展作一綜述。

關鍵詞：青蒿素；青蒿琥酯；弓形蟲感染小鼠；胚胎吸收；大鼠；蒿甲醚；作用機制；劑量相關性；抗瘧藥；金黃地鼠

來源出版物：中國藥房, 2003, 14(2): 118-119

被引頻次：54

超臨界CO2從黃花蒿中提取青蒿素的研究

錢國平，楊亦文，吳彩娟，等

摘要：研究了用超臨界二氧化碳從黃花蒿中萃取青蒿素的影響因素。在152～297 MPa和40～60℃范圍內，萃取壓力和萃取溫度升高，萃取率增大，萃取選擇性下降。以萃取率和萃取選擇性為目標，優化了超臨界萃取工藝條件，得到較佳的操作條件萃取壓力20 MPa，萃取溫度50℃，CO2流量1 kg/（h·kg原料），原料粒徑60～80目。在優化條件下萃取4 h，萃取率達到95%以上，萃取物純度10%以上。

關鍵詞：青蒿素；超臨界二氧化碳；萃??；黃花蒿

來源出版物：化工進展, 2005, 24(3): 286-290

被引頻次：54

青蒿毛狀根合成青蒿素的培養條件研究

劉春朝，王玉春，歐陽藩，等

摘要：對影響青蒿（Artemisia annua L.）毛狀根生長及青蒿素合成的培養條件進行了研究，確定最適的培養條件為：初始PH5.8～6.0，搖瓶轉速130～150 r/min，搖瓶裝液量體積分數為25%，光照周期為16 h/d，溫度為30℃。在此條件下，經過25 d培養獲得青蒿素產量為223.3 mg/L。

來源出版物：植物學報：英文版, 1998, 40(9): 831-835

被引頻次：54

青蒿素理化性質及其測定方法的研究進展

王宗德，孫芳華

摘要：菊科植物黃花蒿（Artemisia annua L，即中藥青蒿）在我國用作抗瘧中藥已有二千多年的歷史。我國科學工作者70年代首次從中分離出一個含過氧基團的新型倍半萜內酯，并命名為青蒿素（Artemisinin；Arteannuin；Qinghaosu；QHS）。國內外大量理化實驗，藥理研究及臨床應用表明，青蒿素是抗瘧的有效成分。其結構獨特，抗瘧機制特別，對抗氯喹的惡性瘧和腦性瘧有特效，正因為它具有結構上的新穎性和藥理作用中高效低毒等特點，國際上有關方面認為青蒿素的發現是抗瘧研究史上的重大突破，并已成為世界衛生組織推薦的抗瘧藥品。

關鍵詞：青蒿素；理化性質；測定方法

來源出版物：江西農業大學學報, 1999, 21(4): 606-611

被引頻次：53

青蒿素介導肝癌細胞凋亡的實驗研究

陳征途，黃真炎，吳玲霓

摘要：目的：探討抗瘧藥青蒿琥酯對肝癌細胞株HepG2的凋亡誘導作用。方法：用MTT測定、流式細胞術、梯狀DNA電泳和透射電鏡術檢測細胞凋亡。結果：經青蒿琥酯處理的HepG2細胞可見梯狀DNA和凋亡小體等典型細胞凋亡特征。當青蒿琥酯濃度（80 μmol/L）接近TC50（74.21 μmol/L）時，HepG2細胞破壞率可達51.76%，細胞凋亡率為19.91%。結論：青蒿琥酯可誘導HepG2細胞凋亡。

關鍵詞：青蒿琥酯；細胞凋亡；肝癌

來源出版物：中西醫結合肝病雜志, 2000, 10(5): 23-25

被引頻次：52

黃花蒿中青蒿素的超臨界CO2流體提取工藝研究

葛發歡，張鏡澄，陳列，等

摘要：研究了用超臨界CO2流體萃取法從黃花蒿中提取青蒿素的工藝，主要探討了壓力、時間、CO2流量等因素對產品收率的影響，確定了最佳工藝條件，并進行了中試放大和工業化試驗，所得產品質量達藥品標準，與傳統生產工藝（如汽油法）相比，收率提高了1.9倍，生產周期縮短近100 h，生產成本降低了447 元/kg。

關鍵詞：超臨界CO2萃??；青蒿素；工藝研究；工業化試驗

來源出版物：中國醫藥工業雜志, 2000, 31(6): 250-253

被引頻次：52

青蒿素類藥物的藥理作用新進展

郭燕，王俊，陳正堂

摘要：青蒿素是從植物黃花蒿中提取的抗瘧疾的活性成份，目前在臨床上廣泛用于治療瘧疾。近些年研究發現青蒿素不僅可以抗寄生蟲，包括瘧原蟲、血吸蟲，而且具有顯著的抗炎、調節免疫和抗腫瘤等多方面的藥理作用。本文在介紹青蒿素抗瘧疾作用、應用和作用機制的基礎上，對近年來青蒿素類藥物的其它主要生物學作用研究的現狀進行綜述。

關鍵詞：青蒿素；抗瘧疾；抗腫瘤；膿毒癥；抗寄生蟲

來源出版物：中國臨床藥理學與治療學, 2006, 11(6): 615-620

被引頻次：1400

Qinghaosu (Artemisinin): An antimalarial drug from China

Klayman, DL

Abstract: The herb Artemisia annua has been used for many centuries in Chinese traditional medicine as a treatment for fever and malaria.In 1971, Chinese chemists isolated from the leafy portions of the plant the substance responsible for its reputed medicinal action.This compound, called qinghaosu (QHS, artemisinin), is a sesquiterpene lactone that bears a peroxide grouping and, unlike most other antimalarials, lacks a nitrogen-containing heterocyclic ring system.The compound has been used successfully in several thousand malaria patients in China, including those with both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum.Derivatives of QHS, such as dihydroqinghaosu, artemether, and the water-soluble sodium artesunate, appear to be more potent than QHS itself.Sodium artesunate acts rapidly in restoring to consciousness comatose patients with cerebral malaria.Thus QHS and its derivatives offer promise as a totally new class of antimalarials.

來源出版物：Science, 1985, 228(4703): 1049-1055

被引頻次：1091

Artemisinin resistance in Plasmodium falciparum malaria

Dondorp, AM; Nosten, F; Yi, P; et al.

Abstract: Background: Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in allcountries with endemic disease.There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance.Methods: In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram.We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance.Results: We studied 40 patients in each of the two locations.The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001).Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P=0.31).These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P.falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]).Adverse events were mild and did not differ significantly between the two treatment groups.Conclusions: P.falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand.Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing.Containment measures are urgently needed.

Keywords: Artesunate-mefloquine; Artemether-lumefantrine; combination therapy; in-vitro; Thailand; Cambodia; border; efficacy; epidemiology; deployment

來源出版物：New England Journal of Medicine, 2009, 361(5): 455-467

被引頻次：941

Production of the antimalarial drug precursor artemisinic acid in engineered yeast

Ro, DK; Paradise, EM; Ouellet, M

Abstract: Malaria is a global health problem that threatens 300-500 million people and kills more than one million people annually(1).Disease control is hampered by the occurrence of multi-drug-resistant strains of the malaria parasite Plasmodium falciparum(2,3).Synthetic antimalarial drugs and malarial vaccines are currently being developed, but their efficacy against malaria awaits rigorous clinical testing(4,5).Artemisinin, a sesquiterpene lactone endoperoxide extracted from Artemisia annua L (family Asteraceae; commonly known as sweet wormwood), is highly effective against multi-drug-resistant Plasmodium spp., but is in short supply and unaffordable to most malaria sufferers(6).Although total synthesis of artemisinin is difficult and costly(7), the semi-synthesis of artemisinin or any derivative from microbially sourced artemisinic acid, its immediate precursor, could be a cost-effective, environmentally friendly, high-quality and reliable source of artemisinin(8,9).Here we report the engineering of Saccharomyces cerevisiae to produce high titres (up to 100 mg L-1) of artemisinic acid using an engineered mevalonate pathway, amorphadiene synthase, and a novel cytochrome P450 monooxygenase (CYP71AV1) from A.annua that performs a three-step oxidation of amorpha-4,11-diene to artemisinic acid.The synthesized artemisinic acid is transported out and retained on the outside of the engineered yeast, meaning that a simple and inexpensive purification process can be used to obtain the desired product.Although the engineered yeast is already capable of producing artemisinic acid at a significantly higher specific productivity than A.annua, yield optimization and industrial scale-up will be required to raise artemisinic acid production to a level high enough to reduce artemisinin combination therapies to significantly below their current prices.

Keywords: catalyzes 3 steps; gibberellin biosynthesis; Saccharomyces-cerevisiae; expression; malaria; pathway; cytochrome-p450; identification; reductase; oxidase

來源出版物：Nature, 2006, 440(7086): 940-943

被引頻次：534

Artemisinins target the SERCA of Plasmodium falciparum

Eckstein-Ludwig, U; Webb, RJ; van Goethem, IDA; et al.

Abstract: Artemisinins are extracted from sweet wormwood (Artemisia annua) and are the most potent antimalarials available(1), rapidly killing all asexual stages of Plasmodium falciparum(2).Artemisinins are sesquiterpene lactones widely used to treat multidrug-resistant malaria(1), a disease that annually claims 1 million lives.Despite extensive clinical and laboratory experience(3-5) their molecular target is not yet identified.Activated artemisinins form adducts with a variety of biological macromolecules, including haem, translationally controlled tumour protein (TCTP) and other higher-molecular-weight proteins(6).Here we show that artemisinins, but not quinine or chloroquine, inhibit the SERCA orthologue (PfATP6) of Plasmodium falciparum in Xenopus oocytes with similar potency to thapsigargin (another sesquiterpene lactone and highly specific SERCA inhibitor).As predicted, thapsigargin also antagonizes the parasiticidal activity of artemisinin.Desoxyartemisinin lacks an endoperoxide bridge and is ineffective both as an inhibitor of PfATP6 and as an antimalarial.Chelation of iron by desferrioxamine abrogates the antiparasitic activity of artemisinins and correspondingly attenuates inhibition of PfATP6.Imaging of parasites with BODIPY-thapsigargin labels the cytosolic compartment and is competed by artemisinin.Fluorescent artemisinin labels parasites similarly and irreversibly in an Fe2+-dependent manner.These data provide compelling evidence that artemisinins act by inhibiting PfATP6 outside the food vacuole after activation by iron.

Keywords: calcium-pump; antimalarial; derivatives; malaria; in vitro; resistance; reticulum; qinghaosu; parasite; drugs

來源出版物：Nature, 2003, 424(6951): 957-961

被引頻次：421

Qinghaosu

Zhang, H; Wu, J; Zhang, J; et al.

Abstract: In December, 1979, an extraordinary paper in the Chinese Medical Journa[1 chronicled the discovery and evaluation of a group of antimalarial drugs derived from the Chinese medicinal herb qing hao (Artemisia annua L).This plant, also known as annual or sweet wormwood, is widely distributed in Europe, North America, India, and Eastern Asia.Medicinal use of qing hao (as a treatment for haemorrhoids!) was first described in the “52 Prescriptions” unearthed in 168 BC from the Mawangdui Han dynasty tomb in Changsha, Hunan province.The herb was specifically recommended for fevers in the Zhou Hou Bei Ji Fang, a handbook of prescriptions for emergencies written by Ge Heng and published in 341 AD.Thereafter qing hao appears in several standard Chinese materia medica texts as a treatment for febrile illnesses.

Keywords: acute falciparum-malaria; antimalarial activity; oral quinine; artemisinin; mefloquine; dihydroartemisinin; suppositories; drugs

來源出版物：The Lancet, 1993, 341(8845): 603-608

被引頻次：396

Artesunate versus quinine for treatment of severe falciparum malaria: A randomised trial

Faiz, MA; Bin Yunus, E; Rahman, MR

Abstract: Background: In the treatment of severe malaria, intravenous artesunate is more rapidly acting than intravenous quinine in terms of parasite clearance, is safer, and is simpler to administer, but whether it can reduce mortality is uncertain.Methods: We did an open-label randomised controlled trial in patients admitted to hospital with severe falciparum malaria in Bangladesh, India, Indonesia, and Myanmar.We assigned individuals intravenous artesunate 2.4 mg/kg bodyweight given as a bolus (n=730) at 0, 12, and 24 h, and then daily, or intravenous quinine (20 mg salt per kg loading dose infused over 4 h then 10 mg/kg infused over 2-8 h three times a day; n=731).Oral medication was substituted when possible to complete treatment.Our primary endpoint was death from severe malaria, and analysis was by intention to treat.Findings: We assessed all patients randomised for the primary endpoint.Mortality in artesunate recipients was 15% (107 of 730) compared with 22% (164 of 731) in quinine recipients; an absolute reduction of 34.7% (95% CI 18.5%-47.6%; P=0.0002).Treatment with artesunate was well tolerated, whereas quinine was associated with hypoglycaemia (relative risk 3.2, 1.3-7.8; P=0.009).Interpretation Artesunate should become the treatment of choice for severe falciparum malaria in adults.

Keywords: cerebral malaria; plasmodium-falciparum; intramuscular artesunate; intravenous quinine; antimalarial-drugs; artemether; children; dihydroartemisinin; pharmacokinetics; tetracycline

來源出版物：The Lancet, 2005, 366(9487): 717-725

被引頻次：361

Hydraulic lift - substantial nocturnal water transport between soil layers by artemisia-tridentata roots

Richards, JH; Caldwell, MM

Abstract: Diel soil water potential fluctuations reflected daytime depletion and nocturnal resupply of water in upper soil layers.Transpiration suppression experiments demonstrated that water absorption by roots caused the daytime depletion.The soil water potential data and experimental results suggest that at night water absorbed from moist soil by deeper roots is transported to and lost from roots into drier upper soil layers.The deeper roots appear to absorb and transport water both day and night.Implications for the efficiency of deep roots and water storage, nutrient uptake and water parasitism in upper soil layers are discussed.

Keywords: root water efflux; roots; soil water potential; plant water relations; desert shrubs

來源出版物：Oecologia, 1987, 73(4): 486-489

被引頻次：324

Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: A prospective study

Nosten, F; van Vugt, M; Price, R; et al.

Abstract: Background: Worsening drug resistance in Plasmodium falciparum malaria is a major threat to health in tropical countries.Wedid a prospective study of malaria incidence and treatment in an area of highly multidrug-resistant P falciparum malaria.Methods: We assessed incidence of P falciparum malaria and the in-vivo responses to mefloquine treatment over 13 years in two large camps for displaced Karen people on the northwest border of Thailand.During this time, the standard mefloquine dose was first increased, and then combined artesunate and mefloquine was introduced as first-line treatment for uncomplicated P falciparum malaria.Findings: Early detection and treatment controlled P falciparum malaria initially while mefloquine was effective (cure rate with mefloquine [15 mg/kg] and sulphadoxine-pyrimethamine in 1985, 98% [95% CI 97-100]), but as mefloquine resistance developed, the cure rate fell (71% [67-77] in 1990).A similar pattern was seen for high-dose (25 mg/kg) mefloquine monotherapy from 1990-94.Since the general deployment of the artesunate-mefloquine combination in 1994, the cure rate increased again to almost 100% from 1998 onwards, and there has been a sustained decline in the incidence of P falciparum malaria in the study area.In-vitro susceptibility of P falciparum to mefloquine has improved significantly (P=0.003).Interpretation: In this area of low malaria transmission, early diagnosis and treatment with combined artesunate and mefloquine has reduced the incidence of P falciparum malaria and halted the progression of mefloquine resistance.We recommend that antimalarial drugs should be combined with artemisinin or a derivative to protect them against resistance.

Keywords: Burmese border; monoclonal-antibodies; elisa development; bed nets; sporozoites; epidemiology; prevention; pregnancy; area

來源出版物：The Lancet, 2000, 356(9226): 297-302

被引頻次：323

Effects of artemisinin derivatives on malaria transmissibility

Price, RN; Nosten, F; Luxemburger, C; et al.

Abstract: Background: On the western border of Thailand the efficacy of mefloquine in the treatment of falciparum malaria has declined while gametocyte carriage rates have increased, which suggests increased transmissibility of these resistant infections.We compared the following antimalarial drugs in relation to subsequent Plasmodium falciparum gametocyte carriage: mefloquine, halofantrine, quinine, and the artemisinin derivatives.Methods: Between 1990 and 1995 we assessed gametocytaemia in a series of prospective studies of antimalarial drug treatment in 5193 adults and children with acute uncomplicated falciparum malaria in an area of malarious hill forest on the western border of Thailand, Weekly parasite counts from thick and thin blood films were done during the 4-week (1990-93) or 9-week (1993-95) follow-up period, Gametocyte positivity rates and person gametocyte week (PGW) rates were calculated to measure gametocyte carriage and transmission potential.Findings: In primary P falciparum infections the gametocyte carriage rate was significantly higher after treatment with mefloquine than after treatment with the artemisinin (PGW 34.1 [95% CI 25.2-42.9] vs 3.9 [1.9-5.9] per 1000 person weeks; relative risk 8.0 [41-156]; P<00001).Recrudescent infections were associated with increased gametocyte carrier rates (relative risk 2.2 [1.6-3.0]; P<0.0001), but retreatment with artemisinin derivatives reduced subsequent gametocyte carriage 18.5 fold [3.5-98] compared with mefloquine retreatment and 6.8 fold (3.1-15.1) compared with quinine retreatment (P<0.001).The introduction of the artemisinin derivatives in routine treatment at this study site in mid 1994 was associated with a reduction in the subsequent incidence of falciparum malaria of 47 (25-69)%.Interpretation: Although environmental changes affect.vector numbers, and hence malaria incidence, artemisinin derivatives were found to reduce the transmission potential of falciparum malaria.Widespread introduction of artemisinin derivatives in the treatment of falciparum malaria may prevent the spread of multidrug resistance.

Keywords: resistant falciparum-malaria; Thai-burmese border; plasmodium-falciparum; mefloquine; pyrimethamine; sulfadoxine; gametocytes

來源出版物：The Lancet, 1996, 347(9016): 1654-1658

被引頻次：307

Artemisinin: Mechanisms of action, resistance and toxicity

Meshnick, SR

Abstract: Artemisinin and its derivatives are widely used throughout the world.The mechanism of action of these compounds appears to involve the heme-mediated decomposition of the endoperoxide bridge to produce carbon-centred free radicals.The involvement of heme explains why the drugs are selectively toxic to malaria parasites.The resulting carbon-centred free radicals are alkylate heme and proteins, one of which is the translationally controlled tumour protein.Clinically relevant artemisinin resistance has not been demonstrated, but it is likely to occur since artemisinin resistance has been obtained in laboratory models.At high doses, artemisinin can be neurotoxic but toxicity has not been found in clinical studies.The mechanism of neurotoxicity may be similar to the mechanism of action.

Keywords: artemisinin; qinghaosu; endoperoxide; antimalarial; malaria; plasmodium

來源出版物：International Journal for Parasitology, 2002, 32(13): 1655-1660

被引頻次：301

Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6

Jambou, R; Legrand, E; Niang, M

Abstract: Artemisinin derivatives are an essential component of treatment against multidrug-resistant Plasmodium falciparum malaria.We aimed to investigate in-vitro resistance to arternisinin derivatives in field isolates.In-vitro susceptibility of 530 P faliciparum isolates from three countries (Cambodia, French Guiana, and Senegal) with different arternisinin use was assessed with an isotopic microtest.Artemether IC50 up to 117 and 45 nmol/L was seen in French Guiana and Senegal, respectively.DNA sequencing in a subsample of 60 isolates lends support to SERCA-PfATPase6 as the target for artemisinins.The S769N PfATPase6 mutation, noted exclusively in French Guiana, was associated with raised (>30 nmol/L) artemether IC(50)s (P<0.0001, Mann-Whitney).All resistant isolates came from areas with uncontrolled use of arternisinin derivatives.This rise in resistance indicates the need for increased vigilance and a coordinated and rapid deployment of drug combinations.

Keywords: susceptibility; chloroquine; artesunate; mefloquine; gene

來源出版物：The Lancet, 2005, 366(9501): 1960-1963

被引頻次：301

Artesunate combinations for treatment of malaria: Meta-analysis

Adjuik, M; Agnamey, P; Babiker, A; et al.

Abstract: Background: Addition of artemisinin derivatives to existing drug regimens for malaria could reduce treatment failure and transmission potential.We assessed the evidence for this hypothesis from randomised controlled trials.Methods: We undertook a meta-analysis of individual patients' data from 16 randomised trials (n=5948) that studied the effects of the addition of artesunate to standard treatment of Plasmodium falciparum malaria.We estimated odds ratios (OR) of parasitological failure at days 14 and 28 (artesunate combination compared with standard treatment) and calculated combined summary ORs across trials using standard methods.Findings: For all trials combined, parasitological failure was lower with 3 days of artesunate at day 14 (OR 0.20, 95% CI 0.17-0.25, n=4504) and at day 28 (excluding new infections, 0.23, 0.19-0.28, n=2908; including re-infections, 0.30, 0.26-0.35, n=4332).Parasite clearance was significantly faster (rate ratio 1.98, 95% CI 1.85-2.12, n=3517) with artesunate.In participants with no gametocytes at baseline, artesunate reduced gametocyte count on day 7 (OR 0.11, 95% CI 0.09-0.15, n=2734), with larger effects at days 14 and 28.Adding artesunate for 1 day (six trials) was associated with fewer failures by day 14 (0.61, 0.48-0.77, n=1980) and day 28 (adjusted to exclude new infections 0.68, 0.53-0.89, n=1205; unadjusted including reinfections 0.77, 0.63-0.95, n=1958).In these trials, gametocytes were reduced by day 7 (in participants with no gametocytes at baseline 0.11, 0.09-0.15, n=2734).The occurrence of serious adverse events did not differ significantly between artesunate and placebo.Interpretation: The addition of 3 days of artesunate to standard antimalarial treatments substantially reduce treatment failure, recrudescence, and gametocyte carriage.

Keywords: plasmodium-falciparum malaria; mefloquine combination; uncomplicated malaria; resistance; trial; amodiaquine; overviews; mortality; children

來源出版物：The Lancet, 2004, 363(9402): 9-17

被引頻次：298

Impact of artemisinin-based combination therapy and insecticide-treated nets on malaria burden in Zanzibar

Bhattarai, Achuyt; Ali, AS; Kachur, SP; et al.

Abstract: Background: The Roll Back Malaria strategy recommends a combination of interventions for malaria control.Zanzibar implemented artemisinin-based combination therapy (ACT) for uncomplicated malaria in late 2003 and long-lasting insecticidal nets (LLINs) from early 2006.ACT is provided free of charge to all malaria patients, while LLINs are distributed free to children under age 5 y (“under five”) and pregnant women.We investigated temporal trends in Plasmodium falciparum prevalence and malaria-related health parameters following the implementation of these two malaria control interventions in Zanzibar.Methods and Findings: Cross-sectional clinical and parasitological surveys in children under the age of 14 y were conducted in North A District in May 2003, 2005, and 2006.Survey data were analyzed in a logistic regression model and adjusted for complex sampling design and potential confounders.Records from all 13 public health facilities in North A District were analyzed for malaria-related outpatient visits and admissions.Mortality and demographic data were obtained from District Commissioner’s Office.P.falciparum prevalence decreased in children under five between 2003 and 2006; using 2003 as the reference year, odds ratios (ORs) and 95% confidence intervals (CIs) were, for 2005, 0.55 (0.28-1.08), and for 2006, 0.03 (0.00-0.27); P for trend<0.001.Between 2002 and 2005 crude under-five, infant ( under age 1 y), and child ( aged 1-4 y) mortality decreased by 52%, 33%, and 71%, respectively.Similarly, malaria-related admissions, blood transfusions, and malaria-attributed mortality decreased significantly by 77%, 67% and 75%, respectively, between 2002 and 2005 in children under five.Climatic conditions favorable for malaria transmission persisted throughout the observational period.Conclusions: Following deployment of ACT in Zanzibar2003, malaria-associated morbidity and mortality decreased dramatically within two years.Additional distribution of LLINs in early 2006 resulted in a 10-fold reduction of malaria parasite prevalence.The results indicate that the Millennium Development Goals of reducing mortality in children under five and alleviating the burden of malaria are achievable in tropical Africa with high coverage of combined malaria control interventions.

Keywords: artemether-lumefantrine; children; mortality; Tanzania

來源出版物：Plos Medicine, 2007, 4(11): 1784-1790

被引頻次：292

Emergence of artemisinin-resistant malaria on the western border of Thailand: A longitudinal study

Phyo, AP; Nkhoma, S; Stepniewska, K; et al.

Abstract: Background: Artemisinin-resistant falciparum malaria has arisen in western Cambodia.A concerted international effort is underway to contain artemisinin-resistant Plasmodium falciparum, but containment strategies are dependent on whether resistance has emerged elsewhere.We aimed to establish whether artemisinin resistance has spread or emerged on the Thailand-Myanmar (Burma) border.Methods: In malaria clinics located along the northwestern border of Thailand, we measured six hourly parasite counts in patients with uncomplicated hyperparasitaemic falciparum malaria (>=4% infected red blood cells) who had been given various oral artesunatecontaining regimens since 2001.Parasite clearance half-lives were estimated and parasites were genotyped for 93 single nucleotide polymorphisms.Findings: 3202 patients were studied between 2001 and 2010.Parasite clearance half-lives lengthened from a geometric mean of 2.6 h (95% CI 2.5-2.7) in 2001, to 3.7 h (3.6-3.8) in 2010, compared with a mean of 5.5 h (5.2-5.9) in 119 patients in western Cambodia measured between 2007 and 2010.The proportion of slow-clearing infections (half-life>= 6.2 h) increased from 0.6% in 2001, to 20% in 2010, compared with 42% in western Cambodia between 2007 and 2010.Of 1583 infections genotyped, 148 multilocus parasite genotypes were identified, each of which infected between two and 13 patients.The proportion of variation in parasite clearance attributable to parasite genetics increased from 30% between 2001 and 2004, to 66% between 2007 and 2010.Interpretation: Genetically determined artemisinin resistance in P falciparum emerged along the Thailand-Myanmar border at least 8 years ago and has since increased substantially.At this rate of increase, resistance will reach rates reported in western Cambodia in 2-6 years.

Keywords: antimalarial-drug resistance; falciparum-malaria; Plasmodium falciparum; multidrug-resistance; parasite clearance; southeast-asia; Cambodia; spread; heritability; artesunate

來源出版物：The Lancet, 2012, 379(9830): 1960-1966

被引頻次：288

Isolation and identification of a senescence-promoting substance from wormwood (Artemisia-absinthium L)

Ueda, J; Kato, J

Abstract: The senescence-promoting substance of wormwood (Artemisia absinthium L.) as detected by the oat (Avena sativa L.cv“Victory”) leaf assay has been identified as (-)-methyl jasmonate, methyl (1S, 2R)-3-oxo-2-(2’-cis-pentenyl)-cyclopentane-1-acetate, by gas-liquid chromatography-mass spectrometry and optical rotatory dispersion.Its senescence-promoting effect was much stronger than that of abscisic acid, and even at such a low concentration as 1 to 2.5 micrograms per milliliter, it could completely eliminate the anti-senescence action of 2 micrograms per milliliter kinetin.Comparing the biological activity of the (-)- with the (±)- forms of methyl jasmonate, it seemed that only the (-)- form was biologically active.

來源出版物：Plant Physiology, 1980, 66(2): 246-249

被引頻次：244

The anti-malarial artesunate is also active against cancer

Efferth, T; Dunstan, H; Sauerbrey, A; et al.

Abstract: Artesunate (ART) is a semi-synthetic derivative of artemisinin, the active principle of the Chinese herb Artemisia annua.ART reveals remarkable activity against otherwise multidrug-resistant Plasmodium falciparum and P.vivax malaria.ART has now been analyzed for its anticancer activity against 55 cell lines of the Developmental Therapeutics Program of the National Cancer Institute, USA.ART was most active against leukemia and colon cancer cell lines (mean GI(50) values: 1.11 +/-0.56 micro M and 2.13 +/-0.74 micro M, respectively).Non-small cell lung cancer cell lines showed the highest mean GI(50) value (25.62 +/- 14.95 micro M) indicating the lowest sensitivity towards NIT in this test panel.Intermediate GI(50) values were obtained for melanomas, breast, ovarian, prostate, CNS, and renal cancer cell lines.Importantly, a comparison of ART's cytotoxicity with those of other standard cytostatic drugs showed that ART was active in molar ranges comparable to those of established anti-tumor drugs.Furthermore, we tested CEM leukemia sub-lines resistant to either doxorubicin, vincristine, methotrexate, or hydroxyurea which do not belong to the N.C.I, screening panel.None of thesedrug-resistant cell lines showed cross resistance to ART.To gain insight into the molecular mechanisms of ART’s cytotoxicity, we used a panel of isogenic Saccaromyces cerevisiae strains with defined genetic mutations in DNA repair, DNA checkpoint and cell proliferation genes.A yeast strain with a defective mitosis regulating BUB3 gene showed increased ART sensitivity and another strain with a defective proliferation-regulating CLN2 gene showed increased ART resistance over the wild-type strain, wt644.None of the other DNA repair or DNA check-point deficient isogenic strains were different from the wildtype.These results and the known low toxicity of ART are clues that ART may be a promising novel candidate for cancer chemotherapy.

Keywords: BUB3; chemotherapy; CLN2; drug resistance; neoplasms; Saccharomyces cerevisiae mutant strains

來源出版物：International Journal of Oncology, 2001, 18(4): 767-773

被引頻次：225

Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): An open-label, randomised trial

Dondorp, AM; Fanello, CI; Hendriksen, ICE; et al.

Abstract: Background: Severe malaria is a major cause of childhood death and often the main reason for paediatric hospital admission in sub Saharan Africa Quinine is still the established treatment of choice, although evidence from Asia suggests that artesunate is associated with a lower mortality We compared parenteral treatment with either artesunate or quinine in African children with severe malaria.Methods: This open label randomised trial was undertaken in 11 centres in nine African countries Children (<15 years) with severe falciparum malaria were randomly assigned to parenteral artesunate or parenteral quinine Randomisation was in blocks of 20, with study numbers corresponding to treatment allocations kept inside opaque sealed paper envelopes The trial was open label at each site, and none of the investigators or trialists apart from for the trial statistician had access to the summaries of treatment allocations The primary outcome measure was in hospital mortality analysed by intention to treat This trial is registered, number ISRCTN50258054.Findings: 5425 children were enrolled 2712 were assigned to artesunate and 2713 to quinine All patients were analysed for the primary outcome 230 (8.5%) patients assigned to artesunate treatment died compared with 297 (10.9%) assigned to quinine treatment (odds ratio [OR] stratified for study site 0.75, 95% CI 0.63-0.90, relative reduction 22.5%, 95% CI 8.1-36.9, P=0.0022) Incidence of neurological sequelae did not differ significantly between groups, but the development of coma (65/1832 [3.5%] with artesunate vs 91/1768 [5.1%] with quinine OR 0.69, 95% CI 0.49-0.95, P=0.0231) convulsions (224/2712 [8.3%] vs 273/2713 [10.1%] OR 0.80, 0.66-0.97 P=0.0199) and deterioration of the coma score (166/2712 [6.1%] vs 208/2713 [7.7%], OR 0.78, 0.64-0.97, P=0.0245) were all significantly less frequent in artesunate recipients than in quinine recipients Post treatment hypoglycaemia was also less frequent in patients assigned to artesunate than in those assigned to quinine (48/2712 [1.8%] vs 75/2713 [2.8%] OR 0.63 0.43-0.91 P=0.0134) Artesunate was well tolerated with no serious drug related adverse effects.Interpretation: Artesunate substantially reduces mortality in African children with severe malaria These data together with a meta analysis of all trials comparing artesunate and quinine, strongly suggest that parenteral artesunate should replace quinine as the treatment of choice for severe falciparum malaria worldwide.

Keywords: cerebral malaria; intramuscular artesunate; intravenous quinine; artemether; dihydroartemisinin; pharmacokinetics; mortality

來源出版物：The Lancet, 2010, 376(9753): 1647-1657

被引頻次：218

Iron-dependent free-radical generation from the antimalarial agent artemisinin (qinghaosu)

Meshnick, SR; Yang, YZ; Lima, V; et al.

Abstract: Artemisinin is an important new antimalarial agent containing a bridged endoperoxide.The in vitro antimalarial activity of an artemisinin derivative, arteether, is antagonized by two iron chelators, pyridoxal benzoylhydrazone and 1,2-dimethyl-3-hydroxypyrid-4-one.Similarly, the acute toxicity of artemisinin in mice is antagonized by another chelator, deferoxamine-hydroxyethylstarch.A combination of artemisinin and hemin oxidizes erythrocyte membrane thiols in vitro, and this oxidation is also inhibited by an iron chelator.Thus, iron plays a role in the mechanisms of action and toxicity of artemisinin.The combination of artemisinin and hemin also decreases erythrocyte deformability.Iron probably catalyzes the generation of free radicals from artemisinin since alpha-tocopherol antagonizes the thiol-oxidizing activity of artemisinin and since a spin-trapped free radical signal can be seen by electron paramagnetic resonance only when artemisinin is incubated in the presence of iron.

Keywords: pyridoxal isonicotinoyl hydrazone; plasmodium-falciparum; cross-linking; hemoglobin; in vitro; malaria; desferrioxamine; erythrocytes; inhibition; chelators

來源出版物：Antimicrobial Agents and Chemotherapy, 1993, 37(5): 1108-1114

被引頻次：215

Amodiaquine-artesunate versus amodiaquine for uncomplicated Plasmodium falciparum malaria in African children: A randomised, multicentre trial

Adjuik, M; Agnamey, P; Babiker, A; et al.

Abstract: Background: Increasing drug resistance limits the choice of efficacious chemotherapy against Plasmodium falciparum malaria in Africa.Amodiaquine still retains efficacy against P falciparum in many African countries.We assessed the safety, treatment efficacy, and effect on gametocyte carriage of adding artesunate to amodiaquine in three randomised trials in Kenya, Senegal, and Gabon.Methods: We enrolled 941 children (400 in Kenya, 321 in Senegal, and 220 in Gabon) who were 10 years or older and who had uncomplicated P falciparum malaria.Patients were randomly assigned amodiaquine (10 mg/kg per day for 3 days) plus artesunate (4 mg/kg per day for 3 days) or amodiaquine (as above) and placebo (for 3 days).The primary endpoints were parasitological cure rates at days 14 and 28.Analysis was by intention to treat and by an evaluability method.Findings: Both regimens were well tolerated.Six patients in the amodiaquine-artesunate group and five in the amodiaquine group developed early, drug-induced vomiting, necessitating alternative treatment.By intention-to-treat analysis, the day-14 cure rates for amodiaquine-artesunate versus amodiaquine were: 175/192 (91%) versus 140/188 (74%) in Kenya (Delta=16.7% [95% CI 9.3-24.1], P<0.0001), 148/160 (93%) versus 147/157 (94%) in Senegal (-1.1% [-6.7 to 4.5], P=0.7), and 92/94 (98%) versus 86/96 (90%) in Gabon (8.3% [1.5-15.1], P=0.02).The corresponding rates for day 28 were: 123/180 (68%) versus 75/183 (41%) in Kenya (27.3% [17.5-37.2], P<0.0001), 130/159 (82%) versus 123/156 (79%) in Senegal (2.9% [-5.9 to 11.7], P=0.5), and 80/94 (85%) versus 70/98 (71%) in Gabon (13.7% [2.2-25.2], P=0.02).Similar rates were obtained by evaluability analysis.Interpretation: The combination of artesunate and amodiaquine improved treatment efficacy in Gabon and Kenya, and was equivalent in Senegal.Amodiaquine-artesunate is a potential combination for use in Africa.Further investigations to assess the potential effect on the evolution of drug resistance, disease transmission, and safety of amodiaquine-artesunate are warranted.

Keywords: pyrimethamine-sulfadoxine; antimalarial drug; double-blind; efficacy; chloroquine; resistance; artemether; benflumetol; combination; CGP-56697

來源出版物：The Lancet, 2002, 359(9315): 1365-1372

被引頻次：211

A molecular marker of artemisinin-resistant Plasmodium falciparum malaria

Frederic A; Witkowski, B; Amaratunga, C; et al.

Abstract: Plasmodium falciparum resistance to artemisinin derivatives in southeast Asia threatens malaria control and elimination activities worldwide.To monitor the spread of artemisinin resistance, a molecular marker is urgently needed.Here, using whole-genome sequencing of an artemisinin-resistant parasite line from Africa and clinical parasite isolates from Cambodia, we associate mutations in the PF3D7_1343700 kelch propeller domain (‘K13-propeller’) with artemisinin resistance in vitro and in vivo.Mutant K13-propeller alleles cluster in Cambodian provinces where resistance is prevalent, and the increasing frequency of a dominant mutant K13-propeller allele correlates with the recent spread of resistance in western Cambodia.Strong correlations between the presence of a mutant allele, in vitro parasite survival rates and in vivo parasite clearance rates indicate that K13-propeller mutations are important determinants of artemisinin resistance.K13-propeller polymorphism constitutes a useful molecular marker for large-scale surveillance efforts to contain artemisinin resistance in the Greater Mekong Subregion and prevent its global spread.

Keywords: kelch-repeat superfamily; in vitro; parasite clearance; western Cambodia; chloroquine resistance; antimalarial-drugs; point mutations; copy number; Keap1; Vivo

來源出版物： Nature, 2014, 505(7481): 50-55

Qinghaosu (artemisinin): An antimalarial drug from China

Klayman, DL

Background: Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease.There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance.Methods: In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: Oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram.We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance.Results: We studied 40 patients in each of the two locations.The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001).Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P=0.31).These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P.falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]).Adverse events were mild and did not differ significantly between the two treatment groups.Conclusions: P.falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand.Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing.Containment measures are urgently needed.Keywords: artesunate-mefloquine; artemether-lumefantrine; combination therapy; in-vitro; Thailand; Cambodia; border; efficacy; epidemiology; deployment來源出版物：New England Journal of Medicine, 2009, 361(5): 455-467Total synthesis of arteannuin and deoxyarteannuinXu, XX; Zhu, J; Huang, DZ ; et al.Abstract: Arteannuin 1 is a new sesquiterpene lactone containing a peroxide linkage and is an antimalarial principle isolated from Artemisia annua L..R(+)-Citronellal 5 as a starting material for the total synthesis was converted into 11R(-)-methyl dihydroarteannuinate 12 in 14 steps.The key intermediate 4 was obtained from compound 12 in 5 steps.The introduction of hydroperoxide in 4 by photooxidation followed by acid treatment gave 1.Hydroxylation of 4 with osmium tetraoxide afforded deoxyarteannuin 2.來源出版物：Tetrahedron, 1986, 42(3): 819-828Iron-dependent free-radical generation from the antimalarial agent artemisinin (qinghaosu)Meshnick, SR; Yang, YZ; Lima, V; et al.Abstract: Artemisinin is an important new antimalarial agent containing a bridged endoperoxide.The in vitro antimalarial activity of an artemisinin derivative, arteether, is antagonized by two iron chelators, pyridoxal benzoylhydrazone and 1,2-dimethyl-3-hydroxypyrid-4-one.Similarly, the acute toxicity of artemisinin in mice is antagonized by another chelator, deferoxamine-hydroxyethylstarch.A combination of artemisinin and hemin oxidizes erythrocyte membrane thiols in vitro, and this oxidation is also inhibited by an iron chelator.Thus, iron plays a role in the mechanisms of action and toxicity of artemisinin.The combination of artemisinin and hemin also decreases erythrocyte deformability.Iron probably catalyzes the generation of free radicals from artemisinin since alpha-tocopherol antagonizes the thiol-oxidizing activity of artemisinin and since a spin-trapped free radical signal can be seen by electron paramagnetic resonance only when artemisinin is incubated in the presence of iron.

pyridoxal isonicotinoyl hydrazone; plasmodium-falciparum; cross-linking; hemoglobin; Invitro; malaria; desferrioxamine; erythrocytes; inhibition; chelators