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Artemisinin resistance

Thunyapit Thita, Pimrat Jadsri, Jarupatr Thamkhantho, Toon Ruang-Areerate, Nantana Suwandittakul, Naruemon Sitthichot, Kittiya Mahotorn, Peerapan Tan-Ariya, Mathirut Mungthin
BACKGROUND: In Thailand, artemisinin-based combination therapy (ACT) has been used to treat uncomplicated falciparum malaria since 1995. Unfortunately, artemisinin resistance has been reported from Thailand and other Southeast Asian countries since 2003. Malarone® , a combination of atovaquone-proguanil (ATQ-PG), has been used to cease artemisinin pressure in some areas along Thai-Cambodia border, as part of an artemisinin resistance containment project since 2009. This study aimed to determine genotypes and phenotypes of Plasmodium falciparum isolates collected from the Thai-Cambodia border after the artemisinin resistance containment project compared with those collected before...
May 15, 2018: Malaria Journal
Mayibongwe J Lunga, Ruramai L Chisango, Carli Weyers, Michelle Isaacs, Dale Taylor, Adrienne L Edkins, Setshaba D Khanye, Heinrich C Hoppe, Clinton Veale
Despite major strides in reducing Plasmodium falciparum infections, this parasite still accounts for roughly half a million annual deaths. This problem is compounded by reduced efficacy of artemisinin combination therapies (ACT). Therefore, the development and optimisation of novel antimalarial chemotypes is critical. In this study, we describe our strategic approach to optimise a class of previously reported antimalarials, resulting in the discovery compounds 13 and 14 whose activity was equipotent to chloroquine against the P...
May 13, 2018: ChemMedChem
Nguyen Ngoc Quang, Marina Chavchich, Chu Xuan Anh, Geoffrey W Birrell, Karin van Breda, Thomas Travers, Kerryn Rowcliffe, Michael D Edstein
The pharmacokinetics (PK) and ex vivo activity (pharmacodynamics [PD]) of two artemisinin combination therapies (ACTs) (artemisinin-piperaquine [ARN-PPQ] [Artequick® ] and artesunate-amodiaquine [ARS-AQ] [Coarsucam™ ]) in healthy Vietnamese volunteers were compared following 3-day courses of the ACTs for the preselection of the drugs for falciparum malaria therapy. For PK analysis, serial plasma samples were collected from two separate groups of 22 volunteers after ACT administration. Of these volunteers, ex vivo activity was assessed in plasma samples from seven volunteers who received both ACTs...
May 7, 2018: American Journal of Tropical Medicine and Hygiene
Zhihan Yao, Adheesh Bhandari, Yinghao Wang, Yiyuan Pan, Fan Yang, Rongfa Chen, Erjie Xia, Ouchen Wang
Although the combination of chemotherapy and surgical resection has effectively increased the survival rate of colorectal cancer patients in recent decades, acquired drug resistance is still a problem that leads to treatment failure. Dihydroartemisinin (DHA), a semisynthetic derivative of artemisinin, has recently been reported to show anticancer effects against numerous types of cancer, including colorectal cancer. This study showed that DHA exerted a strong anticancer effect against several colorectal cancer cell lines...
May 5, 2018: Biochemical and Biophysical Research Communications
Min Zhang, Chengqi Wang, Thomas D Otto, Jenna Oberstaller, Xiangyun Liao, Swamy R Adapa, Kenneth Udenze, Iraad F Bronner, Deborah Casandra, Matthew Mayho, Jacqueline Brown, Suzanne Li, Justin Swanson, Julian C Rayner, Rays H Y Jiang, John H Adams
Severe malaria is caused by the apicomplexan parasite Plasmodium falciparum. Despite decades of research, the distinct biology of these parasites has made it challenging to establish high-throughput genetic approaches to identify and prioritize therapeutic targets. Using transposon mutagenesis of P. falciparum in an approach that exploited its AT-rich genome, we generated more than 38,000 mutants, saturating the genome and defining mutability and fitness costs for over 87% of genes. Of 5399 genes, our study defined 2680 genes as essential for optimal growth of asexual blood stages in vitro...
May 4, 2018: Science
Athanassios Giannis, Johannes Krieger, Toni Smeilus, Marcel Kaiser, Ean-Jeong Seo, Thomas Efferth
Here, we describe an efficient and diversity oriented entry to both (-)-artemisinin (1) and to its natural antipode (+)-artemisinin starting from commercially and readily available S-(+)- and R-(-)-citronellene respectively. Subsequently, we have answered a still open question, i.e. specificity of artemisinins action. Using a drug sensitive Plasmodium falc. NF54 strain we showed that the antimalarial activity of artemisinin is not stereospecific. Our straightforward and biomimetic approach to this natural endoperoxide allows synthesis of artemisinin derivatives not accessible applying current methods and may help to address the problem of emerging resistance of Plasmodium falciparum towards artemisinin...
May 3, 2018: Angewandte Chemie
Kimberly E Mace, Paul M Arguin, Kathrine R Tan
PROBLEM/CONDITION: Malaria in humans is caused by intraerythrocytic protozoa of the genus Plasmodium. These parasites are transmitted by the bite of an infective female Anopheles species mosquito. The majority of malaria infections in the United States occur among persons who have traveled to regions with ongoing malaria transmission. However, malaria is occasionally acquired by persons who have not traveled out of the country through exposure to infected blood products, congenital transmission, laboratory exposure, or local mosquitoborne transmission...
May 4, 2018: MMWR. Surveillance Summaries: Morbidity and Mortality Weekly Report. Surveillance Summaries
Thomas Hanscheid, David W Hardisty
In scientific discourse, few would consider the widely used term resistance as ambiguous. The definition and usage of the term antimicrobial resistance revolves around the concept that microorganisms change in ways that render antimicrobial medications clinically ineffective. Because artemisinins have become the cornerstone for antimalarial therapy, the widely used term artemisinin resistance in scientific literature is highly alarming. Naturally, many people will assume that artemisinin resistance must essentially be the same as antimicrobial resistance, which means it is clinically ineffective...
April 28, 2018: Travel Medicine and Infectious Disease
E Oiknine-Djian, Y Weisblum, A Panet, H N Wong, R K Haynes, D G Wolf
Human cytomegalovirus (HCMV) is a major cause of disease in immunocompromised individuals and the most common cause of congenital infection and neuro-sensorial disease. The expanding target populations for HCMV antiviral treatment along with the limitations of the currently available HCMV DNA polymerase inhibitors underscore the need for new antiviral agents with alternative modes of action. The anti-malarial artemisinin derivative artesunate was shown to inhibit HCMV in vitro , yet has demonstrated limited antiviral efficacy in vivo , prompting our search for more potent anti-HCMV artemisinin derivatives...
April 30, 2018: Antimicrobial Agents and Chemotherapy
Abu Naser Mohon, Didier Menard, Mohammad Shafiul Alam, Kevin Perera, Dylan R Pillai
Background: Artemisinin-resistant malaria (ARM) remains a significant threat to malaria elimination. In the Greater Mekong subregion, the prevalence of ARM in certain regions has reached greater than 90%. Artemisinin-resistant malaria is clinically identified by delayed parasite clearance and has been associated with mutations in the propeller domain of the kelch 13 gene. C580Y is the most prevalent mutation. The detection of ARM currently relies on labor-intensive and time-consuming methods such as clinical phenotyping or in vitro susceptibility testing...
April 2018: Open Forum Infectious Diseases
Erzsébet Domokos, László Jakab-Farkas, Béla Darkó, Béla Bíró-Janka, Gyöngyvér Mara, Csilla Albert, Adalbert Balog
The main objective of this study was to investigate Artemisia annua plant property variations in terms of plant biomass, glandular trichome numbers, artemisinin production and Guaiacol peroxidase (GPOX) activity when plants are in mutualism with AMF. According to the results, A. annua mutualism with AMF significantly increased the most important and pharmaceutically relevant factors of fresh and dry plant biomass. This increase, especially in the biomass of plant herba (leaves), was 30% higher during the vegetation period and remained high (29% higher than for control) when plants were harvested at the end of the vegetation period...
2018: Frontiers in Plant Science
Rebecca S Lee, Andrew P Waters, James M Brewer
Blood stage human malaria parasites may exploit erythropoietic tissue niches and colonise erythroid progenitors; however, the precise influence of the erythropoietic environment on fundamental parasite biology remains unknown. Here we use quantitative approaches to enumerate Plasmodium infected erythropoietic precursor cells using an in vivo rodent model of Plasmodium berghei. We show that parasitised early reticulocytes (ER) in the major sites of haematopoiesis establish a cryptic asexual cycle. Moreover, this cycle is characterised by early preferential commitment to gametocytogenesis, which occurs in sufficient numbers to generate almost all of the initial population of circulating, mature gametocytes...
April 27, 2018: Nature Communications
Jordi Landier, Daniel M Parker, Aung Myint Thu, Khin Maung Lwin, Gilles Delmas, François H Nosten
BACKGROUND: Potentially untreatable Plasmodium falciparum malaria threatens the Greater Mekong subregion. A previous series of pilot projects in Myanmar, Laos, Cambodia, and Vietnam suggested that mass drug administration was safe, and when added to provision of early diagnosis and treatment, could reduce the reservoir of P falciparum and interrupts transmission. We examined the effects of a scaled-up programme of this strategy in four townships of eastern Myanmar on the incidence of P falciparum malaria...
April 24, 2018: Lancet
Hui Liu, Jian-Wei Xu, Qi-Zhang Xu, Yi-Rou Zeng
BACKGROUND: In Myanmar, epidemiological conditions have been unclear due to a lack of accurate data. In 2014 and 2016, malaria outbreaks occurred in the Shan Special Region II (SSR2). It was reported that these outbreaks were caused by malaria patients from the Salween River Valley (SRV), but further research is needed to confirm these reports. To examine the risks of malaria infection in the SSR2 section of the SRV, this paper offers a retrospective analysis based on the data we collected in 2009...
April 27, 2018: BMC Public Health
Pedro H Scarpelli Pereira, Chiara Curra, Celia R S Garcia
Parasites of Plasmodium genus are responsible for causing malaria in humans. Resistant strains to all available antimalarials can be found in several locations around the globe, including parasites resistant to the latest generation of combination drugs, such as piperaquine + artemisinin. Plasmodium develops between two completely different hosts such as a vertebrate one and the mosquito vector, thus it has the ability to adapt to very extreme and different environments. Through the complex life cycle in the hosts, Plasmodium invades and replicates in totally different cells thus making very difficult the study of the biology of the parasite and the identification of targets for drug development affecting all stages...
April 27, 2018: Current Topics in Medicinal Chemistry
Thanat Chookajorn
It is rare to come across an Aesop's fable in respectable journals. It might catch scientists outside the malaria field by surprise to learn that the famous story of "The Boy Who Cried Wolf" has been repeatedly compared to the threat from artemisinin-resistant malaria parasites, including the two latest reports on the rise of a specific haplotype in Cambodia and Thailand, sensationally dubbed "Super Malaria" by the media [1, 2]. The comparison to a children's tale should not negate the fact that malaria drug resistance is one of the most pressing threats to the global public health community...
April 2018: PLoS Pathogens
Lei Zheng, Jingxuan Pan
BACKGROUND: Uveal melanoma is the most common primary intraocular malignancy in adults. So far, there have been no effective targeted therapeutic agents in patients with uveal melanoma. Artesunate is a semi-synthetic derivative of artemisinin extracted from traditional Chinese medicine Artemisia annua L for treatment of severe and multidrug-resistant malaria. Besides its anti-malarial activity, artesunate is identified as an anti-cancer drug due to the inhibition of Wnt/b-catenin pathway in multiple types of cancer...
April 25, 2018: Current Cancer Drug Targets
Laurence Vachot-Ganée, Nimol Khim, Alexandra Iannello, Eric Legrand, Saorin Kim, Rotha Eam, Chanra Khean, Malen Ken, Elizabeth Ashley, Kyaw Myo Tun, Mehul Dhorda, François Nosten, Issa Mahamat Souleymane, Sophie Blein, Alexandre Pachot, Frédéric Ariey, Karine Kaiser, Didier Ménard
BACKGROUND: Given the risk of artemisinin resistance spreading from the Greater Mekong sub-region, prospective monitoring in sub-Saharan Africa should be expedited. Molecular biology techniques used for monitoring rely on the detection of k13 validated mutants by using PCR and Sanger sequencing approach, usually not available in malaria endemic areas. METHODS: A semi-automated workflow based on the easyMAG® platform and the Argene Solution® (bioMérieux, Marcy l'Etoile, France) as a field-based surveillance tool operable at national level was developed in four steps...
April 24, 2018: Malaria Journal
G Lu, M Nagbanshi, N Goldau, M Mendes Jorge, P Meissner, A Jahn, F P Mockenhaupt, O Müller
BACKGROUND: Methylene blue (MB) was the first synthetic antimalarial to be discovered and was used during the late 19th and early 20th centuries against all types of malaria. MB has been shown to be effective in inhibiting Plasmodium falciparum in culture, in the mouse model and in rhesus monkeys. MB was also shown to have a potent ex vivo activity against drug-resistant isolates of P. falciparum and P. vivax. In preclinical studies, MB acted synergistically with artemisinin derivates and demonstrated a strong effect on gametocyte reduction in P...
April 25, 2018: BMC Medicine
Doran Khamis, Claire El Mouden, Klodeta Kura, Michael B Bonsall
BACKGROUND: The sterile insect technique and transgenic equivalents are considered promising tools for controlling vector-borne disease in an age of increasing insecticide and drug-resistance. Combining vector interventions with artemisinin-based therapies may achieve the twin goals of suppressing malaria endemicity while managing artemisinin resistance. While the cost-effectiveness of these controls has been investigated independently, their combined usage has not been dynamically optimized in response to ecological and epidemiological processes...
April 24, 2018: Malaria Journal
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