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Background and objectives: Current tools struggle to detect drug-resistant malaria parasites when infections contain multiple parasite clones, which is the norm in high transmission settings in Africa. Our aim was to develop and apply an approach for detecting resistance that overcomes the challenges of polyclonal infections without requiring a genetic marker for resistance.Methodology: Clinical samples from patients treated with artemisinin combination therapy were collected from Tanzania and Cambodia. By deeply sequencing a hypervariable locus, we quantified the relative abundance of parasite subpopulations (defined by haplotypes of that locus) within infections and revealed evolutionary dynamics during treatment. Slow clearance is a phenotypic, clinical marker of artemisinin resistance; we analyzed variation in clearance rates within infections by fitting parasite clearance curves to subpopulation data.Results: In Tanzania, we found substantial variation in clearance rates within individual patients. Some parasite subpopulations cleared as slowly as resistant parasites observed in Cambodia. We evaluated possible explanations for these data, including resistance to drugs. Assuming slow clearance was a stable phenotype of subpopulations, simulations predicted that modest increases in their frequency could substantially increase time to cure.Conclusions and implications: By characterizing parasite subpopulations within patients, our method can detect rare, slow clearing parasites in vivo whose phenotypic effects would otherwise be masked. Since our approach can be applied to polyclonal infections even when the genetics underlying resistance are unknown, it could aid in monitoring the emergence of artemisinin resistance. Our application to Tanzanian samples uncovers rare subpopulations with worrying phenotypes for closer examination.  相似文献   
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Artemisinin‐based combination therapies (ACTs) are first‐line agents in malaria chemotherapy, but often abused in malaria endemic countries including Nigeria. This study investigated the effects of prolong treatment of artesunate–amodiaquine (ATS–Amod), artesunate‐sulfadoxine‐pyrimethamine (ATS–SP) and artemether–lumefantrine (ATM–Lum) on testicular indices in guinea pigs. Sixty‐five pigs were grouped into 13 (n = 5 per group). Six groups were given standard or double therapeutic dose equivalents of ATS–Amod, ATS‐SP or ATM–Lum daily for 14 day and sacrificed 24 hr after treatments. Six other groups (recovery groups) received similar drug treatments but allowed to recover for 14 day before sacrificed. Control group received distilled water. ATS–Amod, ATS–SP and ATM–Lum, respectively, decreased (< .01) sperm count (17.7%, 37.7% and 33.8%), motility (48.6%, 50% and 51.4%), viability (32.7%, 43.7% and 35.9%) and morphology (123.5%, 0% and 0%), compared to control. These effects were reversed in recovery animals. Also, they decreased (< .01) luteinising hormone and testosterone serum levels, without affecting follicle‐stimulating hormone. Testicular malondialdehyde level was elevated, and glutathione was decreased, while catalase and superoxide dismutase enzymes were unaffected by the drugs. The alterations were all reversed in recovery animals. The study reveals that prolong administration of ACTs results in reversible alteration of sperm parameters and reduction of testosterone which is partly attributable to oxidative stress.  相似文献   
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Artemisinin is one of the most widely prescribed drugs against malaria and has recently received increased attention because of its other potential biological effects. The aim of this review is to summarize recent discoveries of the pharmaceutical effects of artemisinin in basic science along with its mechanistic action, as well as the intriguing results of recent clinical studies, with a focus on its antitumor activity. Scientific evidence indicates that artemisinin exerts its biological activity by generating reactive oxygen species that damage the DNA, mitochondrial depolarization, and cell death. In the present article review, scientific evidence suggests that artemisinin is a potential therapeutic agent for various diseases. Thus, this review is expected to encourage interested scientists to conduct further preclinical and clinical studies to evaluate these biological activities.  相似文献   
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目的 研究低温处理对黄花蒿中青蒿素及其他萜类合成通路的影响。方法 以4 ℃为胁迫条件,利用高效液相色谱法测定青蒿素量;硫酸钛沉淀法和N, N-二甲基-对-亚硝基苯胺漂白反应分别检测黄花蒿叶片过氧化氢(H2O2)和单线态氧(1O2)量;紫外分光光度法检测过氧化氢酶(CAT)活性;实时荧光定量PCR技术定量分析青蒿素合成途径及竞争途径关键酶基因的表达。结果 4 ℃处理4 h后黄花蒿叶片中1O2和H2O2量升高,并伴随着青蒿素量和CAT活性逐步提高,4、24、48 h后青蒿素量分别提高20%、65%、80%;4 ℃处理24 h后,青蒿素合成相关基因(HMGRFPSADSCYP71AV1CPRDBR2)的表达普遍上调,其中ADS基因的表达提高16倍;而青蒿素合成竞争途径酶(β-石竹烯合酶)基因(CS)表达则下调近20倍。结论 低温刺激可能通过产生高浓度活性氧(ROS)促进青蒿素合成前体转化,上调青蒿素合成相关基因表达并抑制竞争途径基因表达等途径促进青蒿素合成。  相似文献   
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BACKGROUND AND PURPOSE Widespread resistance to antimalarial drugs requires combination therapies with increasing risk of pharmacokinetic drug-drug interactions. Here, we explore the capacity of antimalarial drugs to induce drug metabolism via activation of constitutive androstane receptors (CAR) by ligand binding. EXPERIMENTAL APPROACH A total of 21 selected antimalarials and 11 major metabolites were screened for binding to CAR isoforms using cellular and in vitro CAR-coactivator interaction assays, combined with in silico molecular docking. Identified ligands were further characterized by cell-based assays and primary human hepatocytes were used to elucidate induction of gene expression. KEY RESULTS Only two artemisinin derivatives arteether and artemether, the metabolite deoxyartemisinin and artemisinin itself demonstrated agonist binding to the major isoforms CAR1 and CAR3, while arteether and artemether were also inverse agonists of CAR2. Dihydroartemisinin and artesunate acted as weak inverse agonists of CAR1. While arteether showed the highest activities in vitro, it was less active than artemisinin in inducing hepatic CYP3A4 gene expression in hepatocytes. CONCLUSIONS AND IMPLICATIONS Artemisinin derivatives and metabolites differentially affect the activities of CAR isoforms and of the pregnane X receptor (PXR). This negates a common effect of these drugs on CAR/PXR-dependent induction of drug metabolism and further provides an explanation for artemisinin consistently inducing cytochrome P450 genes in vivo, whereas arteether and artemether do not. All these drugs are metabolized very rapidly, but only artemisinin is converted to an enzyme-inducing metabolite. For better understanding of pharmacokinetic drug-drug interaction possibilities, the inducing properties of artemisinin metabolites should be considered.  相似文献   
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Without an effective vaccine for the prevention of malaria, a fundamental component of the strategy for the control of this disease is based on prompt and effective treatment. Due to the high resistance level of Plasmodium falciparum to the most affordable drugs such as chloroquine and sulfadoxine–pyrimethamine, artemisinin-based combination therapies are presently used in many countries or are being developed for registration. One artemisinin combination therapy that is drawing a certain degree of interest is the combination of artesunate (a short half-life drug) plus amodiaquine (a long half-life drug that is presently used in loose combination in many countries). The short half-life drug achieves substantial and rapid parasite killing, while a high concentration of the long half-life drug kills off the remaining malaria parasites. In addition to the effectiveness of 3 days of treatment (rapid clearance of fever and malaria parasites) in western and central Africa, where resistance to amodiaquine is low, the combination of artesunate plus amodiaquine may delay or prevent the emergence of resistance to both drugs. An important step is the recent registration in Morocco (the country where the drug is manufactured) of a fixed combination of artesunate plus amodiaquine by the Drugs for Neglected Diseases initiative with sanofi-aventis as the industrial partner. A prequalification dossier of this fixed combination has been submitted to the WHO. This new co-formulation will almost certainly increase its effectiveness by improving drug compliance.  相似文献   
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Malaria continues to be a major threat in the developing world, with > 1 million clinical episodes and 3000 deaths every day. In the last century, malaria claimed between 150 and 300 million lives, accounting for 2 – 5% of all deaths. Currently ~ 40% of the world population resides in areas of active malaria transmission. The disease symptoms are most severe in young children and pregnant women. A total of 90% of the disease-associated mortality occurs in Subsaharan Africa, despite the fact that malaria is indigenous to most tropical regions. A licensed vaccine for malaria has not become a reality and antimalarial drugs are the only available method of treatment. Although chloroquine, the first synthetically developed antimalarial, proved to be an almost magical cure for > 30 years, the emergence and spread of chloroquine-resistant parasites has made it virtually ineffective in most parts of the world. Currently, artemisinin, a plant-derived antimalarial, is the only available drug that is globally effective against the parasite. Although several new drugs have been introduced in the past 30 years, widespread or isolated cases of resistance indicate that their window of effectiveness will be limited. Thus, there is an urgent need to develop new therapeutics and regimens for malaria control. This article presents an overview of the currently available antimalarial chemotherapy options and the efforts being undertaken to develop new drugs based on both the recent technological advances and modifications to the old remedies, and on combination therapies.  相似文献   
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Following a decade-long scale up of malaria control through vector control interventions, the introduction of rapid diagnostic tests and highly efficacious Artemisinin-based Combination Therapy (ACT) along with other measures, global malaria incidence declined significantly. The recent development of artemisinin resistance on the Cambodia-Thailand border, however, is of great concern. This review encompasses the background of artemisinin resistance in Plasmodium falciparum, its situation, especially in the Greater Mekong Sub-region (GMS), and the responses taken to overcome this resistance. The difficulties in defining resistance are presented, particularly the necessity of measuring the clinical response to artemisinins using the slow parasite-clearance phenotype. Efforts to understand the molecular basis of artemisinin resistance and the search for molecular markers are reviewed. The markers, once identified, can be applied as an efficient tool for resistance surveillance. Despite the limitation of current surveillance methods, it is important to continue vigilance for artemisinin resistance. The therapeutic efficacy “in vivo study'’ network for monitoring antimalarial resistance in the GMS has been strengthened. GMS countries are working together in response to artemisinin resistance and aim to eliminate all P. falciparum parasites. These efforts are crucial since a resurgence of malaria due to drug and/or insecticide resistance, program cuts, lack of political support and donor fatigue could set back malaria control success in the sub-region and threaten malaria control and elimination if resistance spreads to other regions.  相似文献   
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