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Thet Thet Mu, Aye Aye Sein, Tint Tint Kyi, Myo Min, Ne Myo Aung, Nicholas M Anstey, Myat Phone Kyaw, Chit Soe, Mar Mar Kyi, Josh Hanson
BACKGROUND: There has been an impressive recent reduction in the global incidence of malaria, but the development of artemisinin resistance in the Greater Mekong Region threatens this progress. Increasing artemisinin resistance is particularly important in Myanmar, as it is the country in the Greater Mekong Region with the greatest malaria burden. If malaria is to be eliminated in the region, it is essential to define the spatial and temporal epidemiology of the disease in Myanmar to inform control strategies optimally...
October 18, 2016: Malaria Journal
Evelyn K Ansah, Christopher Jm Whitty, Constance Bart-Plange, Margaret Gyapong
BACKGROUND: Most people with febrile illness are treated in the private drug retail sector. Ghana was among nine countries piloting the Global Fund Affordable Medicines Facility - malaria (AMFm). AMFm aimed to: increase artemisinin combination therapy (ACT) affordability; increase ACT availability; increase ACT use; and 'crowd out' artemisinin monotherapies. METHODS: Three censuses were carried out 2 months before (2010), 2 months after and 2.5 years after (2013) the first co-paid ACTs to assess changes in antimalarial (AM) availability and price in private retail shops in a Ghanaian rural district to assess the sustainability of the initial gains...
October 15, 2016: International Health
Zhe Li, Qin Li, Jun Wu, Manyuan Wang, Junxian Yu
Preclinical investigation and clinical experience have provided evidence on the potential anticancer effect of artemisinin and its derivatives (ARTs) in the recent two decades. The major mechanisms of action of ARTs may be due to toxic-free radicals generated by an endoperoxide moiety, cell cycle arrest, induction of apoptosis, and inhibition of tumor angiogenesis. It is very promising that ARTs are expected to be a new class of antitumor drugs of wide spectrum due to their detailed information regarding efficacy and safety...
October 7, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Praveen K Bharti, Man M Shukla, Pascal Ringwald, Sri Krishna, Pushpendra P Singh, Ajay Yadav, Sweta Mishra, Usha Gahlot, Jai P Malaiya, Amit Kumar, Shambhu Prasad, Pradeep Baghel, Mohan Singh, Jaiprakash Vadadi, Mrigendra P Singh, Maria Dorina G Bustos, Leonard I Ortega, Eva-Maria Christophel, Sher S Kashyotia, Gagan S Sonal, Neeru Singh
BACKGROUND: Anti-malarial drug resistance continues to be a leading threat to malaria control efforts and calls for continued monitoring of waning efficacy of artemisinin-based combination therapy (ACT). Artesunate + sulfadoxine/pyrimethamine (AS + SP) is used for the treatment of uncomplicated Plasmodium falciparum malaria in India. However, resistance against AS + SP is emerged in northeastern states. Therefore, artemether-lumefantrine (AL) is the recommended first line treatment for falciparum malaria in north eastern states...
October 13, 2016: Malaria Journal
Gang Liu, Jun Yang, Juan Wang, Xiaohua Liu, Wenjing Huang, Jie Li, Wenfu Tan, Ao Zhang
A series of novel Smo antagonists were developed either by directly incorporating the basic skeleton of the natural product artemisinin or by first breaking artemisinin into structurally simpler and stable intermediates and then reconstructing into diversified heterocyclic derivatives, equipped with a Smo-targeting bullet. 2-(2,5-Dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-arylpropanamide 65 was identified as the most potent with an IC50 value of 9.53 nM against the Hh signaling pathway. Complementary mechanism studies confirmed that 65 inhibits Hh signaling pathway by targeting Smo and shares the same binding site as that of the tool drug cyclopamine...
October 13, 2016: Journal of Medicinal Chemistry
Marija Pinne, Elsa Ponce, Judy L Raucy
The pregnane X receptor (PXR/SXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are nuclear receptors (NRs) involved in the regulation of many genes including cytochrome P450 enzymes (CYPs) and transporters important in metabolism and uptake of both endogenous substrates and xenobiotics. Activation of these receptors can lead to adverse drug effects as well as drug-drug interactions. Depending on which nuclear receptor is activated will determine which adverse effect could occur, making identification important...
2016: PloS One
Cristina Rostkowska, Caroline M Mota, Taísa C Oliveira, Fernanda M Santiago, Lilian A Oliveira, Gaspar H Korndörfer, Regina M Q Lana, Monica L Rossi, Neusa L Nogueira, Xavier Simonnet, Tiago W P Mineo, Deise A O Silva, José R Mineo
Artemisia annua is used as a source of artemisinin, a potent therapeutic agent used for the treatment of infectious diseases, chiefly malaria. However, the low concentration (from 0.01 to 1.4% of dried leaf matter) of artemisinin in the plant obtained with the traditional cropping system makes it a relatively expensive drug, especially in developing countries. Considering that artemisinin and silicon (Si) are both stored in A. annua glandular trichomes, and that Si accumulation has never been investigated, this study aimed to look into Si effects on A...
2016: Frontiers in Plant Science
Beth Williamson, Mathias Lorbeer, Michael D Mitchell, Timothy G Brayman, Robert J Riley
The nuclear pregnane X receptor (PXR) regulates the expression of genes involved in the metabolism, hepatobiliary disposition, and toxicity of drugs and endogenous compounds. PXR is a promiscuous nuclear hormone receptor (NHR) with significant ligand and DNA-binding crosstalk with the constitutive androstane receptor (CAR); hence, defining the precise role of PXR in gene regulation is challenging. Here, utilising a novel PXR-knockout (KO) HepaRG cell line, real-time PCR analysis was conducted to determine PXR involvement for a range of inducers...
October 2016: Pharmacology Research & Perspectives
Chong-Jing Zhang, Jigang Wang, Jianbin Zhang, Yew Mun Lee, Guangxue Feng, Teck Kwang Lim, Han-Ming Shen, Qingsong Lin, Bin Liu
Understanding the mechanism of action (MOA) of bioactive natural products will guide endeavor to improve their cellular activities. Artemisinin and its derivatives inhibit cancer cell proliferation, yet with much lower efficiencies than their roles in killing malaria parasites. To improve their efficacies on cancer cells, we studied the MOA of artemisinin using chemical proteomics and found that free heme could directly activate artemisinin. We then designed and synthesized a derivative, ART-TPP, which is capable of targeting the drug to mitochondria where free heme is synthesized...
October 24, 2016: Angewandte Chemie
Sovannaroth Siv, Arantxa Roca-Feltrer, Seshu Babu Vinjamuri, Denis Mey Bouth, Dysoley Lek, Mohammad Abdur Rashid, Ngau Peng By, Jean Popovici, Rekol Huy, Didier Menard
The Cambodian National Strategic Plan for Elimination of Malaria aims to move step by step toward elimination of malaria across Cambodia with an initial focus on Plasmodium falciparum malaria before achieving elimination of all forms of malaria, including Plasmodium vivax in 2025. The emergence of artemisinin-resistant P. falciparum in western Cambodia over the last decade has drawn global attention to support the ultimate goal of P. falciparum elimination, whereas the control of P. vivax lags much behind, making the 2025 target gradually less achievable unless greater attention is given to P...
October 5, 2016: American Journal of Tropical Medicine and Hygiene
Bridget E Barber, Matthew J Grigg, Timothy William, Tsin W Yeo, Nicholas M Anstey
Plasmodium knowlesi occurs across Southeast Asia and is the most common cause of malaria in Malaysia. High parasitaemias can develop rapidly, and the risk of severe disease in adults is at least as high as in falciparum malaria. Prompt initiation of effective treatment is therefore essential. Intravenous artesunate is highly effective in severe knowlesi malaria and in those with moderately high parasitaemia but otherwise uncomplicated disease. Both chloroquine and artemisinin-combination therapy (ACT) are highly effective for uncomplicated knowlesi malaria, with faster parasite clearance times and lower anaemia rates with ACT...
October 1, 2016: Trends in Parasitology
H Liu, G G Wu, J B Wang, X Wu, L Bai, W Jiang, B B Lv, A H Pan, J W Jia, P Li, K Zhao, L X Jiang, X M Tang
The anti-malarial drug, artemisinin, is quite expensive as a result of its slow content in Artemisia annua. Recent investigations have suggested that genetic engineering of A. annua is a promising approach to improve the yield of artemisinin. In this study, the transgenic A. annua strain GYR, which has high artemisinin content, was evaluated in an environmental release trial. First, GYR plants were compared with the wild-type variety NON-GYR, with regard to phenotypic characters (plant height, crown width, stem diameter, germination rate, leaf dry weight, 1000-seed weight, leave shape)...
August 26, 2016: Genetics and Molecular Research: GMR
Reyaud Rahman, Maria Jesus Sanchez Martin, Shamdeo Persaud, Nicolas Ceron, Dwayne Kellman, Lise Musset, Keith H Carter, Pascal Ringwald
Because of concerns about possible emergence of artemisinin resistance strains of Plasmodium falciparum in mining areas of the interior of Guyana, a 7-day artesunate trial was conducted from March to December 2014. The day-3 parasite clearance rate, the efficacy of artesunate at day 28, and polymorphism of Kelch 13 (PfK13)-the marker of artemisinin resistance-were assessed. The study confirmed the continued sensitivity of P falciparum to artemisinin. A 7-day course of artesunate was 100% efficacious with only 2% (95% confidence interval, ...
September 2016: Open Forum Infectious Diseases
Amélie Le Bihan, Ruben de Kanter, Iñigo Angulo-Barturen, Christoph Binkert, Christoph Boss, Reto Brun, Ralf Brunner, Stephan Buchmann, Jeremy Burrows, Koen J Dechering, Michael Delves, Sonja Ewerling, Santiago Ferrer, Christoph Fischli, Francisco Javier Gamo-Benito, Nina F Gnädig, Bibia Heidmann, María Belén Jiménez-Díaz, Didier Leroy, Maria Santos Martínez, Solange Meyer, Joerg J Moehrle, Caroline L Ng, Rintis Noviyanti, Andrea Ruecker, Laura María Sanz, Robert W Sauerwein, Christian Scheurer, Sarah Schleiferboeck, Robert Sinden, Christopher Snyder, Judith Straimer, Grennady Wirjanata, Jutta Marfurt, Ric N Price, Thomas Weller, Walter Fischli, David A Fidock, Martine Clozel, Sergio Wittlin
BACKGROUND: Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented...
October 2016: PLoS Medicine
Justin A Green, Khadeeja Mohamed, Navin Goyal, Samia Bouhired, Azra Hussaini, Siôn W Jones, Gavin C K W Koh, Ivan Kostov, Maxine Taylor, Allen Wolstenholm, Stephan Duparc
Tafenoquine is in development as a single-dose treatment for relapse prevention in Plasmodium vivax malaria. Tafenoquine must be co-administered with a blood schizonticide; either chloroquine or artemisinin-based combination therapy (ACT). This open-label, randomized, parallel-group study evaluated potential drug interactions between tafenoquine and two ACTs: dihydroartemisinin-piperaquine or artemether-lumefantrine. Healthy volunteers of either sex, aged 18-65 years, without glucose-6-phosphate dehydrogenase deficiency, were randomized into five cohorts (n=24 per cohort) to receive tafenoquine on day 1 (300 mg) plus: once daily dihydroartemisinin-piperaquine on days 1, 2 and 3 (120:960 mg for 36-<75 kg bodyweight; 160:1280 mg for ≥75-100 kg bodyweight); or artemether-lumefantrine (80:480 mg) two doses 8 h apart on day 1, then twice daily on days 2 and 3; or each drug given alone...
October 3, 2016: Antimicrobial Agents and Chemotherapy
Hana Čipčić Paljetak, Linda Tomašković, Mario Matijašić, Mirjana Bukvić, Andrea Fajdetić, Donatella Verbanac, Mihaela Perića
5-LOX - 5-lipoxygenase; ACT - artemisinin-based combination therapies; ADME - absorption, distribution, metabolism and excretion; BAL - broncho alveolar lavage; CABP - community acquired bacterial pneumonia; cAMP - cyclic adenosine monophosphate; CAP - community-acquired pneumonia; CF - cystic fibrosis, BOS bronchiolitis obliterans syndrome; cGMP - cyclic guanosine monophosphate; COPD - chronic obstructive pulmonary disease; COX - cyclooxygenase; DPB - diffuse panbronchiolitis; HDACs - histone deacetylases; IBD - inflammatory bowel disease; IL-1p - interleukin 1p; IL-6 - interleukin 6; MIC - minimal inhibitory concentrations; MLSB - macrolide, lincosamide, streptogramin B; NSAIDs - non-steroidal anti-inflammatory drugs; OVA - ovalbumin; PDE4 - phosphodiesterase 4; PMA - phorbol 12-myristate 13-acetate; RA - rheumatoid arthritis; RTI - respiratory tract infections; SAHA - suberoylanilide hydroxamic acid; SAR - structure-activity-relationship; Th1 - type 1 helper T-cell; TNBS - trinitrobenzene sulfonic acid; TNF-α - tumour necrosis factor α; UN - United Nations, WHO - World Health Organisation...
September 27, 2016: Current Topics in Medicinal Chemistry
Theresa Tawiah, Kristian Schultz Hansen, Frank Baiden, Jane Bruce, Mathilda Tivura, Rupert Delimini, Seeba Amengo-Etego, Daniel Chandramohan, Seth Owusu-Agyei, Jayne Webster
BACKGROUND: The presumptive approach of confirming malaria in health facilities leads to over-diagnosis of malaria, over use of anti-malaria drugs and the risk of drug resistance development. WHO recommends parasitological confirmation before treatment with artemisinin-based combination therapy (ACT) in all suspected malaria patients. The use of malaria rapid diagnostic tests (mRDTs) would make it possible for prescribers to diagnose malaria at point-of-care and better target the use of antimalarials...
2016: PloS One
Zenglei Wang, Mynthia Cabrera, Jingyun Yang, Lili Yuan, Bhavna Gupta, Xiaoying Liang, Karen Kemirembe, Sony Shrestha, Awtum Brashear, Xiaolian Li, Stephen F Porcella, Jun Miao, Zhaoqing Yang, Xin-Zhuan Su, Liwang Cui
Drug resistance has emerged as one of the greatest challenges facing malaria control. The recent emergence of resistance to artemisinin (ART) and its partner drugs in ART-based combination therapies (ACT) is threatening the efficacy of this front-line regimen for treating Plasmodium falciparum parasites. Thus, an understanding of the molecular mechanisms that underlie the resistance to ART and the partner drugs has become a high priority for resistance containment and malaria management. Using genome-wide association studies, we investigated the associations of genome-wide single nucleotide polymorphisms with in vitro sensitivities to 10 commonly used antimalarial drugs in 94 P...
October 3, 2016: Scientific Reports
Jun Sun, Chen Li, Suwen Wang
The current theories of antimalarial mechanism of artemisinin are inadequate to fully explain the observed effects. In our study, "organism-like" formation of Schistosoma hemozoin granules by attaching to and utilizing erythrocytes to form new ones was observed. This indicates that heme iron is transferred from erythrocytes to hemozoin granules during their formation. However, as a disposal product of heme detoxification, these granules are not completely expelled from the Schistosoma gut, but decomposed again between microvilli in the posterior portion of the gut to transfer iron to eggs...
October 3, 2016: Scientific Reports
M M Ouldabdallahi, O Sarr, L K Basco, S M Lebatt, B Lo, O Gaye
BACKGROUND: Until 2006, the Mauritanian Ministry of Health recommended chloroquine and sulfadoxine-pyrimethamine for first- and second-line treatment of uncomplicated malaria, respectively. This study assessed the clinical efficacy of sulfadoxine-pyrimethamine in Kobeni as first-line treatment. MATERIALS AND METHODS: This study included 55 patients with Plasmodium falciparum infections, who were treated with sulfadoxine-pyrimethamine and followed up for 28 days...
August 1, 2016: Médecine et Santé Tropicales
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