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Special Issue "Artemisinin (Qinghaosu): Commemorative Issue in Honor of Professor Youyou Tu on the Occasion of her 80th Anniversary"

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (15 December 2009)

Special Issue Editor

Guest Editor
Dr. Geoff Brown

Department of Chemistry, The University of Reading, Whiteknights, Reading, RG6 6AD, UK
Website | E-Mail
Fax: +44 (0) 118 378 6331
Interests: *for Molecules specifically*: natural products; terpenes; biosynthesis; autoxidation chemistry; structure determination by NMR spectroscopy; prebiotic chemistry; *for Pharmaceuticals specifically*: natural products; antimalarial drugs; cannabinoids; NMR spectroscopy; metabonomics; oligosacharide structure determination

Published Papers (12 papers)

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Editorial

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Open AccessEditorial Discovery of Artemisinin (Qinghaosu)
Molecules 2009, 14(12), 5362-5366; doi:10.3390/molecules14125362
Received: 9 December 2009 / Accepted: 18 December 2009 / Published: 21 December 2009
Cited by 16 | PDF Full-text (110 KB)
Abstract
Artemisinin (Qinghaosu), a new antimalarial drug, was discovered in China in the early 1970s. The discovery of artemisinin is attributed to You-You Tu, at that time a middle-aged phytochemist working in the Institute of Chinese Materia Medica, China Academy of Traditional Chinese Medicine.
[...] Read more.
Artemisinin (Qinghaosu), a new antimalarial drug, was discovered in China in the early 1970s. The discovery of artemisinin is attributed to You-You Tu, at that time a middle-aged phytochemist working in the Institute of Chinese Materia Medica, China Academy of Traditional Chinese Medicine. The following paragraph provides a brief summary of her discovery. [...] Full article

Research

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Open AccessArticle A Simplified Liquid Chromatography-Mass Spectrometry Assay for Artesunate and Dihydroartemisinin, Its Metabolite, in Human Plasma
Molecules 2010, 15(12), 8747-8768; doi:10.3390/molecules15128747
Received: 18 October 2010 / Revised: 13 November 2010 / Accepted: 27 November 2010 / Published: 1 December 2010
Cited by 10 | PDF Full-text (443 KB)
Abstract
Artesunate (AS) is a potent antimalarial that is used worldwide for the treatment of malaria. A simple method with a total run time of 12 min was developed and validated for the quantification of AS and dihydroartemisinin (DHA), its active metabolite, in human
[...] Read more.
Artesunate (AS) is a potent antimalarial that is used worldwide for the treatment of malaria. A simple method with a total run time of 12 min was developed and validated for the quantification of AS and dihydroartemisinin (DHA), its active metabolite, in human (heparinized) plasma based on one-step protein precipitation in acetonitrile using artemisinin (ARN) as an internal standard, followed by liquid chromatography with a single quadrupole mass spectrometry system connected to a C18 column. Peak area ratio responses were fitted to the 2nd-order curve type, polynomial equation with weighting (1/concentration) over a quantification range between 3.20/5.33–3,000/5,000 nM (1.23/1.52–1153/1422 ng/mL) of AS/DHA showing linearity with very good correlation (r2 > 0.999). Single ion recordings of 5 µL injections of plasma extracts allowed for limits of detection of 1.02 nM (0.39 ng/mL) for AS and 0.44 nM (0.13 ng/mL) for DHA. The inter-assay and intra-assay accuracy and precision of the method was very good with an inaccuracy of ±12.4% and coefficients of variation of ≤10.7% at all tested concentrations. The recovery of the analytes from plasma was ≥95%. Other commonly used antimalarials including mefloquine, quinine, and chloroquine, did not interfere with the analysis. Post-preparative tests over 24 h in an autosampler (10 °C) showed that the DHA response was only 2.1% of AS from auto-hydrolysis, and β-DHA was the major, stable epimer that was used for quantification of DHA. In contrast, α-DHA increased steadily up to 600%. Artesunate and DHA in plasma were stable through three freeze/thaw cycles for up to 6 h at room temperature and up to one year at -80 °C. Full article
Open AccessArticle Pharmacogenomic Identification of c-Myc/Max-Regulated Genes Associated with Cytotoxicity of Artesunate towards Human Colon, Ovarian and Lung Cancer Cell Lines
Molecules 2010, 15(4), 2886-2910; doi:10.3390/molecules15042886
Received: 26 March 2010 / Revised: 20 April 2010 / Accepted: 22 April 2010 / Published: 22 April 2010
Cited by 23 | PDF Full-text (624 KB)
Abstract
Development of novel therapy strategies is one of the major pressing topics of clinical oncology to overcome drug resistance of tumors. Artesunate (ART) is an anti-malarial drug, which also exerts profound cytotoxic activity towards cancer cells. We applied a gene-hunting approach using microarray-based
[...] Read more.
Development of novel therapy strategies is one of the major pressing topics of clinical oncology to overcome drug resistance of tumors. Artesunate (ART) is an anti-malarial drug, which also exerts profound cytotoxic activity towards cancer cells. We applied a gene-hunting approach using microarray-based transcriptome-wide mRNA expression profiling and COMPARE analyses. We identified a set of genes, whose expression was associated either with high IC50 values or low IC50 values for ART. Therefore, these genes may function as resistance or sensitivity factors for response of tumor cells towards ART. This viewpoint is conceivable for genes involved in ribosomal activity, drug transport, cellular antioxidant defense, apoptosis, cell proliferation, cell cycle progression etc. An investigation of underlying signal transduction by pathway analysis suggested a role of the signaling pathways related to tumor necrosis factor (TNF) and the tumor suppressor p53. On the other hand, there were genes without obvious functional link to cellular response to ART, such as genes involved in the survival of cochlear outer and inner hair cells etc. We proved the hypothesis that ART influences the activity of transcription factors regulating downstream genes involved or not involved in response of cancer cells towards ART. This would explain the identification of genes with and without obvious relation to the cytotoxic activity of ART by microarray and COMPARE analyses. By analysis of the binding motifs for the transcription factors c-Myc and Max, we indeed found that 53 of 56 genes contained one or more binding sites for c-Myc/Max upstream of the gene-location. We conclude that c-Myc and Max-mediated transcriptional control of gene expression might contribute to the therapeutic effects of ART in cancer cells, but may also confer unwanted side effects by affecting therapy-unrelated genes. Full article
Open AccessArticle Effect of Sugars on Artemisinin Production in Artemisia annua L.: Transcription and Metabolite Measurements
Molecules 2010, 15(4), 2302-2318; doi:10.3390/molecules15042302
Received: 16 December 2009 / Revised: 20 March 2010 / Accepted: 23 March 2010 / Published: 30 March 2010
Cited by 21 | PDF Full-text (233 KB)
Abstract
The biosynthesis of the valuable sesquiterpene anti-malarial, artemisinin, is known to respond to exogenous sugar concentrations. Here young Artemisia annua L. seedlings (strain YU) were used to measure the transcripts of six key genes in artemisinin biosynthesis in response to growth on sucrose,
[...] Read more.
The biosynthesis of the valuable sesquiterpene anti-malarial, artemisinin, is known to respond to exogenous sugar concentrations. Here young Artemisia annua L. seedlings (strain YU) were used to measure the transcripts of six key genes in artemisinin biosynthesis in response to growth on sucrose, glucose, or fructose. The measured genes are: from the cytosolic arm of terpene biosynthesis, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), farnesyl disphosphate (FPS); from the plastid arm of terpene biosynthesis, 1-deoxyxylulose-5-phosphate synthase (DXS), 1-deoxyxylulouse 5-phosphate reductoisomerase (DXR); from the dedicated artemisinin pathway amorpha-4,11-diene synthase (ADS), and the P450, CYP71AV1 (CYP). Changes in intracellular concentrations of artemisinin (AN) and its precursors, dihydroartemisinic acid (DHAA), artemisinic acid (AA), and arteannuin B (AB) were also measured in response to these three sugars. FPS, DXS, DXR, ADS and CYP transcript levels increased after growth in glucose, but not fructose. However, the kinetics of these transcripts over 14 days was very different. AN levels were significantly increased in glucose-fed seedlings, while levels in fructose-fed seedlings were inhibited; in both conditions this response was only observed for 2 days after which AN was undetectable until day 14. In contrast to AN, on day 1 AB levels doubled in seedlings grown in fructose compared to those grown in glucose. Results showed that transcript level was often negatively correlated with the observed metabolite concentrations. When seedlings were gown in increasing levels of AN, some evidence of a feedback mechanism emerged, but mainly in the inhibition of AA production. Together these results show the complex interplay of exogenous sugars on the biosynthesis of artemisinin in young A. annua seedlings. Full article
Open AccessArticle Ancient Chinese Methods Are Remarkably Effective for the Preparation of Artemisinin-Rich Extracts of Qing Hao with Potent Antimalarial Activity
Molecules 2010, 15(2), 804-812; doi:10.3390/molecules15020804
Received: 11 January 2010 / Revised: 29 January 2010 / Accepted: 3 February 2010 / Published: 4 February 2010
Cited by 26 | PDF Full-text (123 KB)
Abstract
Ancient Chinese herbal texts as far back as the 4th Century Zhou hou bei ji fang describe methods for the use of Qing Hao (Artemisia annua) for the treatment of intermittent fevers. Today, the A. annua constituent artemisinin is an important
[...] Read more.
Ancient Chinese herbal texts as far back as the 4th Century Zhou hou bei ji fang describe methods for the use of Qing Hao (Artemisia annua) for the treatment of intermittent fevers. Today, the A. annua constituent artemisinin is an important antimalarial drug and the herb itself is being grown and used locally for malaria treatment although this practice is controversial. Here we show that the ancient Chinese methods that involved either soaking, (followed by wringing) or pounding, (followed by squeezing) the fresh herb are more effective in producing artemisinin-rich extracts than the usual current method of preparing herbal teas from the dried herb. The concentrations of artemisinin in the extracts was up to 20-fold higher than that in a herbal tea prepared from the dried herb, but the amount of total artemisinin extracted by the Chinese methods was much less than that removed in the herbal tea. While both extracts exhibited potent in vitro activities against Plasmodium falciparum, only the pounded juice contained sufficient artemisinin to suppress parasitaemia in P. berghei infected mice. The implications of these results are discussed in the context of malaria treatment using A. annua infusions. Full article
Open AccessArticle New 1-Aryl-3-Substituted Propanol Derivatives as Antimalarial Agents
Molecules 2009, 14(10), 4120-4135; doi:10.3390/molecules14104120
Received: 11 August 2009 / Revised: 21 September 2009 / Accepted: 14 October 2009 / Published: 14 October 2009
Cited by 10 | PDF Full-text (147 KB)
Abstract
This paper describes the synthesis and in vitro antimalarial activity against a P. falciparum 3D7 strain of some new 1-aryl-3-substituted propanol derivatives. Twelve of the tested compounds showed an IC50 lower than 1 μM. These compounds were also tested for cytotoxicity in
[...] Read more.
This paper describes the synthesis and in vitro antimalarial activity against a P. falciparum 3D7 strain of some new 1-aryl-3-substituted propanol derivatives. Twelve of the tested compounds showed an IC50 lower than 1 μM. These compounds were also tested for cytotoxicity in murine J774 macrophages. The most active compounds were evaluated for in vivo activity against P. berghei in a 4-day suppressive test. Compound 12 inhibited more than 50% of parasite growth at a dose of 50 mg/kg/day. In addition, an FBIT test was performed to measure the ability to inhibit ferriprotoporphyrin biocrystallization. This data indicates that 1-aryl-3-substituted propanol derivatives hold promise as a new therapeutic option for the treatment of malaria. Full article
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Review

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Open AccessReview The Biosynthesis of Artemisinin (Qinghaosu) and the Phytochemistry of Artemisia annua L. (Qinghao)
Molecules 2010, 15(11), 7603-7698; doi:10.3390/molecules15117603
Received: 13 September 2010 / Accepted: 17 October 2010 / Published: 28 October 2010
Cited by 106 | PDF Full-text (1398 KB)
Abstract
The Chinese medicinal plant Artemisia annua L. (Qinghao) is the only known source of the sesquiterpene artemisinin (Qinghaosu), which is used in the treatment of malaria. Artemisinin is a highly oxygenated sesquiterpene, containing a unique 1,2,4-trioxane ring structure, which is responsible for the
[...] Read more.
The Chinese medicinal plant Artemisia annua L. (Qinghao) is the only known source of the sesquiterpene artemisinin (Qinghaosu), which is used in the treatment of malaria. Artemisinin is a highly oxygenated sesquiterpene, containing a unique 1,2,4-trioxane ring structure, which is responsible for the antimalarial activity of this natural product. The phytochemistry of A. annua is dominated by both sesquiterpenoids and flavonoids, as is the case for many other plants in the Asteraceae family. However, A. annua is distinguished from the other members of the family both by the very large number of natural products which have been characterised to date (almost six hundred in total, including around fifty amorphane and cadinane sesquiterpenes), and by the highly oxygenated nature of many of the terpenoidal secondary metabolites. In addition, this species also contains an unusually large number of terpene allylic hydroperoxides and endoperoxides. This observation forms the basis of a proposal that the biogenesis of many of the highly oxygenated terpene metabolites from A. annua – including artemisinin itself – may proceed by spontaneous oxidation reactions of terpene precursors, which involve these highly reactive allyllic hydroperoxides as intermediates. Although several studies of the biosynthesis of artemisinin have been reported in the literature from the 1980s and early 1990s, the collective results from these studies were rather confusing because they implied that an unfeasibly large number of different sesquiterpenes could all function as direct precursors to artemisinin (and some of the experiments also appeared to contradict one another). As a result, the complete biosynthetic pathway to artemisinin could not be stated conclusively at the time. Fortunately, studies which have been published in the last decade are now providing a clearer picture of the biosynthetic pathways in A. annua. By synthesising some of the sesquiterpene natural products which have been proposed as biogenetic precursors to artemisinin in such a way that they incorporate a stable isotopic label, and then feeding these precursors to intact A. annua plants, it has now been possible to demonstrate that dihydroartemisinic acid is a late-stage precursor to artemisinin and that the closely related secondary metabolite, artemisinic acid, is not (this approach differs from all the previous studies, which used radio-isotopically labelled precursors that were fed to a plant homogenate or a cell-free preparation). Quite remarkably, feeding experiments with labeled dihydroartemisinic acid and artemisinic acid have resulted in incorporation of label into roughly half of all the amorphane and cadinane sesquiterpenes which were already known from phytochemical studies of A. annua. These findings strongly support the hypothesis that many of the highly oxygenated sesquiterpenoids from this species arise by oxidation reactions involving allylic hydroperoxides, which seem to be such a defining feature of the chemistry of A. annua. In the particular case of artemisinin, these in vivo results are also supported by in vitro studies, demonstrating explicitly that the biosynthesis of artemisinin proceeds via the tertiary allylic hydroperoxide, which is derived from oxidation of dihydroartemisinic acid. There is some evidence that the autoxidation of dihydroartemisinic acid to this tertiary allylic hydroperoxide is a non-enzymatic process within the plant, requiring only the presence of light; and, furthermore, that the series of spontaneous rearrangement reactions which then convert this allylic hydroperoxide to the 1,2,4-trioxane ring of artemisinin are  also non-enzymatic in nature. Full article
Open AccessReview Flavonoids from Artemisia annua L. as Antioxidants and Their Potential Synergism with Artemisinin against Malaria and Cancer
Molecules 2010, 15(5), 3135-3170; doi:10.3390/molecules15053135
Received: 26 January 2010 / Revised: 8 April 2010 / Accepted: 19 April 2010 / Published: 29 April 2010
Cited by 124 | PDF Full-text (280 KB)
Abstract
Artemisia annua is currently the only commercial source of the sesquiterpene lactone artemisinin.Since artemisinin was discovered as the active component of A. annua in early 1970s, hundreds of papers have focused on the anti-parasitic effects of artemisinin and its semi-synthetic analogs dihydroartemisinin, artemether,
[...] Read more.
Artemisia annua is currently the only commercial source of the sesquiterpene lactone artemisinin.Since artemisinin was discovered as the active component of A. annua in early 1970s, hundreds of papers have focused on the anti-parasitic effects of artemisinin and its semi-synthetic analogs dihydroartemisinin, artemether, arteether, and artesunate. Artemisinin per se has not been used in mainstream clinical practice due to its poor bioavailability when compared to its analogs. In the past decade, the work with artemisinin-based compounds has expanded to their anti-cancer properties. Although artemisinin is a major bioactive component present in the traditional Chinese herbal preparations (tea), leaf flavonoids, also present in the tea, have shown a variety of biological activities and may synergize the effects of artemisinin against malaria and cancer. However, only a few studies have focused on the potential synergistic effects between flavonoids and artemisinin. The resurgent idea that multi-component drug therapy might be better than monotherapy is illustrated by the recent resolution of the World Health Organization to support artemisinin-based combination therapies (ACT), instead of the previously used monotherapy with artemisinins. In this critical review we will discuss the possibility that artemisinin and its semi-synthetic analogs might become more effective to treat parasitic diseases (such as malaria) and cancer if simultaneously delivered with flavonoids. The flavonoids present in A. annua leaves have been linked to suppression of CYP450 enzymes responsible for altering the absorption and metabolism of artemisinin in the body, but also have been linked to a beneficial immunomodulatory activity in subjects afflicted with parasitic and chronic diseases. Full article
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Open AccessReview The Molecular Mechanism of Action of Artemisinin—The Debate Continues
Molecules 2010, 15(3), 1705-1721; doi:10.3390/molecules15031705
Received: 14 January 2010 / Revised: 23 February 2010 / Accepted: 9 March 2010 / Published: 12 March 2010
Cited by 190 | PDF Full-text (417 KB)
Abstract
Despite international efforts to ‘roll back malaria’ the 2008 World Malaria Report revealed the disease still affects approximately 3 billion people in 109 countries; 45 within the WHO African region. The latest report however does provide some ‘cautious optimism’; more than one third
[...] Read more.
Despite international efforts to ‘roll back malaria’ the 2008 World Malaria Report revealed the disease still affects approximately 3 billion people in 109 countries; 45 within the WHO African region. The latest report however does provide some ‘cautious optimism’; more than one third of malarious countries have documented greater than 50% reductions in malaria cases in 2008 compared to 2000. The goal of the Member States at the World Health Assembly and ‘Roll Back Malaria’ (RBM) partnership is to reduce the numbers of malaria cases and deaths recorded in 2000 by 50% or more by the end of 2010. Although malaria is preventable it is most prevalent in poorer countries where prevention is difficult and prophylaxis is generally not an option. The burden of disease has increased by the emergence of multi drug resistant (MDR) parasites which threatens the use of established and cost effective antimalarial agents. After a major change in treatment policies, artemisinins are now the frontline treatment to aid rapid clearance of parasitaemia and quick resolution of symptoms. Since artemisinin and its derivatives are eliminated rapidly, artemisinin combination therapies (ACT’s) are now recommended to delay resistance mechanisms. In spite of these precautionary measures reduced susceptibility of parasites to the artemisinin-based component of ACT’s has developed at the Thai-Cambodian border, a historical ‘hot spot’ for MDR parasite evolution and emergence. This development raises serious concerns for the future of the artemsinins and this is not helped by controversy related to the mode of action. Although a number of potential targets have been proposed the actual mechanism of action remains ambiguous. Interestingly, artemisinins have also shown potent and broad anticancer properties in cell lines and animal models and are becoming established as anti-schistosomal agents. In this review we will discuss the recent evidence explaining bioactivation and potential molecular targets in the chemotherapy of malaria and cancer. Full article
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Open AccessReview Biological Actions of Artemisinin: Insights from Medicinal Chemistry Studies
Molecules 2010, 15(3), 1378-1397; doi:10.3390/molecules15031378
Received: 13 January 2010 / Revised: 23 February 2010 / Accepted: 2 March 2010 / Published: 8 March 2010
Cited by 36 | PDF Full-text (212 KB)
Abstract
Artemisinins have become essential antimalarial drugs for increasingly widespread drug-resistant malaria strains. Although tremendous efforts have been devoted to decipher how this class of molecules works, their exact antimalarial mechanism is still an enigma. Several hypotheses have been proposed to explain their actions,
[...] Read more.
Artemisinins have become essential antimalarial drugs for increasingly widespread drug-resistant malaria strains. Although tremendous efforts have been devoted to decipher how this class of molecules works, their exact antimalarial mechanism is still an enigma. Several hypotheses have been proposed to explain their actions, including alkylation of heme by carbon-centered free radicals, interference with proteins such as the sarcoplasmic/endoplasmic calcium ATPase (SERCA), as well as damaging of normal mitochondrial functions. Besides artemisinins, other endoperoxides with various backbones have also been synthesized, some of which showed comparable or even higher antimalarial effects. It is noteworthy that among these artemisinin derivatives, some enantiomers displayed similar in vitro malaria killing efficacy. In this article, the proposed mechanisms of action of artemisinins are reviewed in light of medicinal chemistry findings characterized by efficacy-structure studies, with the hope of gaining more insight into how these potent drugs work. Full article
Open AccessReview Stereodynamic Investigation of Labile Stereogenic Centres in Dihydroartemisinin
Molecules 2010, 15(3), 1309-1323; doi:10.3390/molecules15031309
Received: 1 January 2010 / Revised: 25 January 2010 / Accepted: 4 March 2010 / Published: 5 March 2010
Cited by 10 | PDF Full-text (379 KB)
Abstract
Since its identification in the early 1970s, artemisinin, as well as semi-synthetic derivatives and synthetic trioxanes, have been used in malaria therapy. Reduction of artemisinin by NaBH4 produced dihydroartemisinin (DHA), and yielded a new stereochemically labile centre at C-10, which, in turn,
[...] Read more.
Since its identification in the early 1970s, artemisinin, as well as semi-synthetic derivatives and synthetic trioxanes, have been used in malaria therapy. Reduction of artemisinin by NaBH4 produced dihydroartemisinin (DHA), and yielded a new stereochemically labile centre at C-10, which, in turn, provided two interconverting lactol hemiacetal epimers (namely a and b), whose rate of interconversion depends on buffer, pH, and solvent polarity. Since interconversion of the two epimers occurred on a chromatographic time-scale, this prompted a thorough investigation of the phenomenon as a crucial requisite of any analytical method aimed at quantitating this family of drugs. In this critical review we discuss the current importance of the on-column epimerization of DHA in the development of analytical methods aimed at quantifying the drug, with the purpose of identifying the optimal conditions to minimize on-column epimerization while achieving the best selectivity and efficiency of the overall separation. Full article
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Open AccessReview Severe Embryotoxicity of Artemisinin Derivatives in Experimental Animals, but Possibly Safe in Pregnant Women
Molecules 2010, 15(1), 40-57; doi:10.3390/molecules15010040
Received: 16 November 2009 / Revised: 22 December 2009 / Accepted: 24 December 2009 / Published: 25 December 2009
Cited by 15 | PDF Full-text (180 KB)
Abstract
Preclinical studies in rodents have demonstrated that artemisinins, especially injectable artesunate, can induce fetal death and congenital malformations at a low dose range. The embryotoxicity can be induced in those animals only within a narrow window in early embryogenesis. Evidence was presented that
[...] Read more.
Preclinical studies in rodents have demonstrated that artemisinins, especially injectable artesunate, can induce fetal death and congenital malformations at a low dose range. The embryotoxicity can be induced in those animals only within a narrow window in early embryogenesis. Evidence was presented that the mechanism by which embryotoxicity of artemisinins occurs seems to be limited to fetal erythropoiesis and vasculogenesis/ angiogenesison the very earliest developing red blood cells, causing severe anemia in the embryos with higher drug peak concentrations. However, this embryotoxicity has not been convincingly observed in clinical trials from 1,837 pregnant women, including 176 patients in the first trimester exposed to an artemisinin agent or artemisinin-based combination therapy (ACT) from 1989 to 2009. In the rodent, the sensitive early red cells are produced synchronously over one day with single or multiple exposures to the drug can result in a high proportion of cell deaths. In contrast, primates required a longer period of treatment of 12 days to induce such embryonic loss. In humans only limited information is available about this stage of red cell development; however, it is known to take place over a longer time period, and it may well be that a limited period of treatment of 2 to 3 days for malaria would not produce serious toxic effects. In addition, current oral intake, the most commonly used route of administration in pregnant women with an ACT, results in lower peak concentration and shorter exposure time of artemisinins that demonstrated that such a concentration–course profile is unlikely to induce the embryotoxicity. When relating the animal and human toxicity of artemisinins, the different drug sensitive period and pharmacokinetic profiles as reviewed in the present report may provide a great margin of safety in the pregnant women. Full article

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