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Artemisinin resistance

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https://www.readbyqxmd.com/read/28635296/benzoxaborole-antimalarial-agents-part-5-lead-optimization-of-novel-amide-pyrazinyloxy-benzoxaboroles-and-identification-of-a-preclinical-candidate
#1
Yong-Kang Zhang, Jacob J Plattner, Eric E Easom, Robert Toms Jacobs, Denghui Guo, Yvonne R Freund, Pamela Berry, Vic Ciaravino, John C L Erve, Philip J Rosenthal, Brice Campo, Francisco-Javier Gamo, Laura M Sanz, Jianxin Cao
Carboxamide pyrazinyloxy benzoxaboroles were investigated with the goal to identify a molecule with satisfactory antimalarial activity, physicochemical properties, pharmacokinetic profile, in vivo efficacy, and safety profile. This optimization effort discovered 46, which met our target candidate profile. Compound 46 had excellent activity against cultured Plasmodium falciparum, and in vivo against P. falciparum and P. berghei in infected mice. It exhibited good PK properties in mouse, rat and dog. It was highly active against other eleven P...
June 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28634831/malaria-2017-update-on-the-clinical-literature-and-management
#2
REVIEW
Johanna P Daily
PURPOSE OF REVIEW: Malaria is a prevalent disease in travelers to and residents of malaria-endemic regions. Health care workers in both endemic and non-endemic settings should be familiar with the latest evidence for the diagnosis, management and prevention of malaria. This article will discuss the recent malaria epidemiologic and medical literature to review the progress, challenges, and optimal management of malaria. RECENT FINDINGS: There has been a marked decrease in malaria-related global morbidity and mortality secondary to malaria control programs over the last few decades...
June 20, 2017: Current Infectious Disease Reports
https://www.readbyqxmd.com/read/28620813/an-in-silico-insight-into-the-substrate-binding-characteristics-of-the-active-site-of-amorpha-4-11-diene-synthase-a-key-enzyme-in-artemisinin-biosynthesis
#3
Habib Eslami, Seyed Kaveh Mohtashami, Maryam Taghavi Basmanj, Maryam Rahati, Hamzeh Rahimi
The enzyme amorphadiene synthase (ADS) conducts the first committed step in the biosynthetic conversion of the substrate farnesyl pyrophosphate (FPP) to artemisinin, which is a highly effective natural product against multidrug-resistant strains of malaria. Due to the either low abundance or low turn-over rate of the enzyme, obtaining artemisinin from both natural and synthetic sources is costly and laborious. In this in silico study, we strived to elucidate the substrate binding site specificities of the ADS, with the rational that unraveling enzyme features paves the way for enzyme engineering to increase synthesis rate...
July 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28615016/ex-vivo-susceptibility-and-genotyping-of-plasmodium-falciparum-isolates-from-pikine-senegal
#4
Aminata Mbaye, Amy Gaye, Baba Dieye, Yaye D Ndiaye, Amy K Bei, Muna Affara, Awa B Deme, Mamadou S Yade, Khadim Diongue, Ibrahima M Ndiaye, Tolla Ndiaye, Mouhamed Sy, Ngayo Sy, Ousmane Koita, Donald J Krogstad, Sarah Volkman, Davis Nwakanma, Daouda Ndiaye
BACKGROUND: The monitoring of Plasmodium falciparum sensitivity to anti-malarial drugs is a necessity for effective case management of malaria. This species is characterized by a strong resistance to anti-malarial drugs. In Senegal, the first cases of chloroquine resistance were reported in the Dakar region in 1988 with nearly 7% population prevalence, reaching 47% by 1990. It is in this context that sulfadoxine-pyrimethamine temporarily replaced chloroquine as first line treatment in 2003, pending the introduction of artemisinin-based combination therapy in 2006...
June 14, 2017: Malaria Journal
https://www.readbyqxmd.com/read/28599096/proteases-as-antimalarial-targets-strategies-for-genetic-chemical-and-therapeutic-validation
#5
REVIEW
Edgar Deu
Malaria is a devastating parasitic disease affecting half of the world's population. The rapid emergence of resistance against new antimalarial drugs, including artemisinin-based therapies, has made the development of drugs with novel mechanisms of action extremely urgent. Proteases are enzymes proven to be well suited for target-based drug development due to our knowledge of their enzymatic mechanisms and active site structures. More importantly, Plasmodium proteases have been shown to be involved in a variety of pathways that are essential for parasite survival...
June 9, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28594879/molecular-surveillance-of-plasmodium-falciparum-resistance-to-artemisinin-based-combination-therapies-in-the-democratic-republic-of-congo
#6
Dieudonné Makaba Mvumbi, Thierry Lengu Bobanga, Jean-Marie Ntumba Kayembe, Georges Lelo Mvumbi, Hippolyte Nani-Tuma Situakibanza, Françoise Benoit-Vical, Pierrette Melin, Patrick De Mol, Marie-Pierre Hayette
Malaria is a major public health problem in the Democratic Republic of Congo. Despite progress achieved over the past decade in the fight against malaria, further efforts have to be done such as in the surveillance and the containment of Plasmodium falciparum resistant strains. We investigated resistance to artemisinin-based combination therapies currently in use in Democratic Republic of Congo by surveying molecular polymorphisms in three genes: pfcrt, pfmdr1 and pfk13 to explore possible emergence of amodiaquine, lumefantrine or artemisinin resistance in Democratic Republic of Congo...
2017: PloS One
https://www.readbyqxmd.com/read/28591198/single-dose-primaquine-to-reduce-gametocyte-carriage-and-plasmodium-falciparum-transmission-in-cambodia-an-open-label-randomized-trial
#7
Jessica T Lin, Chanthap Lon, Michele D Spring, Somethy Sok, Soklyda Chann, Mali Ittiverakul, Worachet Kuntawunginn, Mok My, Kheangheng Thay, Rifat Rahman, Sujata Balasubramanian, Mengchuor Char, Charlotte A Lanteri, Panita Gosi, Ratawan Ubalee, Steven R Meshnick, David L Saunders
BACKGROUND: Single low dose primaquine (SLD PQ, 0.25mg/kg) is recommended in combination with artemisinin-based combination therapy (ACT) as a gametocytocide to prevent Plasmodium falciparum transmission in areas threatened by artemisinin resistance. To date, no randomized controlled trials have measured primaquine's effect on infectiousness to Anopheline mosquitoes in Southeast Asia. METHODS: Cambodian adults with uncomplicated falciparum malaria were randomized to receive a single 45mg dose of primaquine (equivalent to three SLD PQ) or no primaquine after the third dose of dihydroartemisin-piperaquine (DHP) therapy...
2017: PloS One
https://www.readbyqxmd.com/read/28589330/triple-combination-therapy-and-drug-cycling-tangential-strategies-for-countering-artemisinin-resistance
#8
REVIEW
Bhattacharjee Dipanjan, G Shivaprakash, O Balaji
PURPOSE OF REVIEW: This review attempts to understand the reasons for the successes and failures of the two novel strategies that have slowly begun to emerge as potential counters for anti-malarial drug resistance-"Triple Combination Therapy" and "Drug Cycling." RECENT FINDINGS: Recent reports have suggested that increasing the heterogeneity within the parasite's environment, both at an individual and the population level, may help raise the probabilistic barrier of development of resistance in the parasite...
July 2017: Current Infectious Disease Reports
https://www.readbyqxmd.com/read/28580606/combating-multi-drug-resistant-plasmodium-falciparum-malaria
#9
REVIEW
Aung Myint Thu, Aung Pyae Phyo, Jordi Landier, Daniel M Parker, François H Nosten
Over the past 50 years, P. falciparum has developed resistance against all antimalarial drugs used against it: chloroquine, sulphadoxine-pyrimethamine, quinine, piperaquine and mefloquine. More recently, resistance to the artemisinin derivatives and the resulting failure of artemisinin based combination therapy (ACT) are threatening all major gains made in malaria control. Each time resistance has developed over a progression, with delayed clearance of parasites emerging in a few regions, increasing in prevalence and geographic range, and then ultimately resulting in the complete failure of that antimalarial...
June 5, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28571765/potential-of-synthetic-endoperoxides-against-trichomonas-vaginalis-in-vitro
#10
Min-Young Seo, Jae-Sook Ryu, Akira Sato, Yuji Kurosaki, Kyung Soo Chang, Hye-Sook Kim
Metronidazole is well known for medicine against Trichomonas vaginalis infection, but it has side effects though it is effective, and especially because reports of metronidazole-tolerant species are increasing, the development of new medicine is being required. Here, we noticed the killing effects of endoperoxide compounds, N-89 and N-251 as new antimalarial drug candidates, on T. vaginalis and searched the possibility of development of new medicine. We added each of metronidazole, artemisinin, and two of new endoperoxides (N-89 and N-251) to metronidazole-resistant and -sensitive species and compared its anti-trichomonal efficacy...
May 29, 2017: Parasitology International
https://www.readbyqxmd.com/read/28566563/isolation-of-dihydroartemisinic-acid-from-the-artemisia-annua-l-by-product-by-combining-ultrasound-assisted-extraction-with-response-surface-methodology
#11
Shuoqian Liu, Jorge Freire da Silva Ferreira, Liping Liu, Yuwei Tang, Dongming Tian, Zhonghua Liu, Na Tian
Malaria is the most devastating parasitic disease worldwide. Artemisinin is the only drug that can cure malaria that is resistant to quinine-derived drugs. After the commercial extraction of artemisinin from Artemisia annua, the recovery of DHAA (dihydroartemisinic acid) from artemisinin extraction by-product has the potential to increase artemisinin commercial yield. Here we describe the development and optimization of an ultrasound-assisted alkaline procedure for the extraction of DHAA from artemisinin production waste using response surface methodology...
June 1, 2017: Chemical & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28549390/clinical-and-molecular-monitoring-of-plasmodium-falciparum-resistance-to-antimalarial-drug-artesunate-sulphadoxine-pyrimethamine-in-two-highly-malarious-district-of-madhya-pradesh-central-india-from-2012-2014
#12
Sweta Mishra, Praveen K Bharti, Man M Shukla, Nazia A Ali, Sher S Kashyotia, Avdhesh Kumar, Akshay C Dhariwal, Neeru Singh
The spread of P. falciparum resistant strain has led to a significant resurgence of malaria morbidity and mortality. The current cornerstone in malaria treatment in India is Artemisinin based Combination (Artesunate + Sulphadoxine-Pyrimethamine) Therapy (ACT) for treatment of uncomplicated P. falciparum malaria since 2010. In the present study we assessed the therapeutic efficacy of ACT and molecular monitoring of antimalarial resistance. Therapeutic efficacy was determined by in vivo method using 28 days follow-up...
May 26, 2017: Pathogens and Global Health
https://www.readbyqxmd.com/read/28546554/high-throughput-resistance-profiling-of-plasmodium-falciparum-infections-based-on-custom-dual-indexing-and-illumina-next-generation-sequencing-technology
#13
Sidsel Nag, Marlene D Dalgaard, Poul-Erik Kofoed, Johan Ursing, Marina Crespo, Lee O'Brien Andersen, Frank Møller Aarestrup, Ole Lund, Michael Alifrangis
Genetic polymorphisms in P. falciparum can be used to indicate the parasite's susceptibility to antimalarial drugs as well as its geographical origin. Both of these factors are key to monitoring development and spread of antimalarial drug resistance. In this study, we combine multiplex PCR, custom designed dual indexing and Miseq sequencing for high throughput SNP-profiling of 457 malaria infections from Guinea-Bissau, at the cost of 10 USD per sample. By amplifying and sequencing 15 genetic fragments, we cover 20 resistance-conferring SNPs occurring in pfcrt, pfmdr1, pfdhfr, pfdhps, as well as the entire length of pfK13, and the mitochondrial barcode for parasite origin...
May 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28542123/malaria-surveillance-united-states-2014
#14
Kimberly E Mace, Paul M Arguin
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 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 26, 2017: MMWR. Surveillance Summaries: Morbidity and Mortality Weekly Report. Surveillance Summaries
https://www.readbyqxmd.com/read/28539634/the-plasmodium-pi-4-k-inhibitor-kdu691-selectively-inhibits-dihydroartemisinin-pretreated-plasmodium-falciparum-ring-stage-parasites
#15
L Dembele, X Ang, M Chavchich, G M C Bonamy, J J Selva, M Yi-Xiu Lim, C Bodenreider, B K S Yeung, F Nosten, B M Russell, M D Edstein, J Straimer, D A Fidock, T T Diagana, P Bifani
Malaria control and elimination are threatened by the emergence and spread of resistance to artemisinin-based combination therapies (ACTs). Experimental evidence suggests that when an artemisinin (ART)-sensitive (K13 wild-type) Plasmodium falciparum strain is exposed to ART derivatives such as dihydroartemisinin (DHA), a small population of the early ring-stage parasites can survive drug treatment by entering cell cycle arrest or dormancy. After drug removal, these parasites can resume growth. Dormancy has been hypothesized to be an adaptive physiological mechanism that has been linked to recrudescence of parasites after monotherapy with ART and, possibly contributes to ART resistance...
May 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28539125/do-anti-malarials-in-africa-meet-quality-standards-the-market-penetration-of-non-quality-assured-artemisinin-combination-therapy-in-eight-african-countries
#16
Paul N Newton, Kara Hanson, Catherine Goodman
BACKGROUND: Quality of artemisinin-based combination therapy (ACT) is important for ensuring malaria parasite clearance and protecting the efficacy of artemisinin-based therapies. The extent to which non quality-assured ACT (non-QAACT), or those not granted global regulatory approval, are available and used to treat malaria in endemic countries is poorly documented. This paper uses national and sub-national medicine outlet surveys conducted in eight study countries (Benin, Kinshasa and Kantanga [Democratic Republic of the Congo, DRC], Kenya, Madagascar, Nigeria, Tanzania, Uganda and Zambia) between 2009 and 2015 to describe the non-QAACT market and to document trends in availability and distribution of non-QAACT in the public and private sector...
May 25, 2017: Malaria Journal
https://www.readbyqxmd.com/read/28537265/a-tetraoxane-based-antimalarial-drug-candidate-that-overcomes-pfk13-c580y-dependent-artemisinin-resistance
#17
Paul M O'Neill, Richard K Amewu, Susan A Charman, Sunil Sabbani, Nina F Gnädig, Judith Straimer, David A Fidock, Emma R Shore, Natalie L Roberts, Michael H-L Wong, W David Hong, Chandrakala Pidathala, Chris Riley, Ben Murphy, Ghaith Aljayyoussi, Francisco Javier Gamo, Laura Sanz, Janneth Rodrigues, Carolina Gonzalez Cortes, Esperanza Herreros, Iñigo Angulo-Barturén, María Belén Jiménez-Díaz, Santiago Ferrer Bazaga, María Santos Martínez-Martínez, Brice Campo, Raman Sharma, Eileen Ryan, David M Shackleford, Simon Campbell, Dennis A Smith, Grennady Wirjanata, Rintis Noviyanti, Ric N Price, Jutta Marfurt, Michael J Palmer, Ian M Copple, Amy E Mercer, Andrea Ruecker, Michael J Delves, Robert E Sinden, Peter Siegl, Jill Davies, Rosemary Rochford, Clemens H M Kocken, Anne-Marie Zeeman, Gemma L Nixon, Giancarlo A Biagini, Stephen A Ward
K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P...
May 24, 2017: Nature Communications
https://www.readbyqxmd.com/read/28535801/molecular-markers-of-anti-malarial-drug-resistance-in-central-west-and-east-african-children-with-severe-malaria
#18
Christian N Nguetse, Ayola Akim Adegnika, Tsiri Agbenyega, Bernhards R Ogutu, Sanjeev Krishna, Peter G Kremsner, Thirumalaisamy P Velavan
BACKGROUND: The Plasmodium falciparum multidrug resistance 1 (PfMDR1), P. falciparum Ca(2+)-ATPase (PfATP6) and Kelch-13 propeller domain (PfK13) loci are molecular markers of parasite susceptibility to anti-malarial drugs. Their frequency distributions were determined in the isolates collected from children with severe malaria originating from three African countries. METHODS: Samples from 287 children with severe malaria [(Gabon: n = 114); (Ghana: n = 89); (Kenya: n = 84)] were genotyped for pfmdr1, pfatp6 and pfk13 loci by DNA sequencing and assessing pfmdr1 copy number variation (CNV) by real-time PCR...
May 23, 2017: Malaria Journal
https://www.readbyqxmd.com/read/28533790/aapdr3-a-pdr-transporter-3-is-involved-in-sesquiterpene-%C3%AE-caryophyllene-transport-in-artemisia-annua
#19
Xueqing Fu, Pu Shi, Qian He, Qian Shen, Yueli Tang, Qifang Pan, Yanan Ma, Tingxiang Yan, Minghui Chen, Xiaolong Hao, Pin Liu, Ling Li, Yuliang Wang, Xiaofen Sun, Kexuan Tang
Artemisinin, a sesquiterpenoid endoperoxide, isolated from the plant Artemisia annua L., is widely used in the treatment of malaria. Another sesquiterpenoid, β-caryophyllene having antibiotic, antioxidant, anticarcinogenic and local anesthetic activities, is also presented in A. annua. The role played by sesquiterpene transporters in trichomes and accumulation of these metabolites is poorly understood in A. annua and in trichomes of other plant species. We identified AaPDR3, encoding a pleiotropic drug resistance (PDR) transporter located to the plasma membrane from A...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28533179/polymorphisms-in-pfdhfr-and-pfdhps-genes-after-five-years-of-artemisinin-combination-therapy-act-implementation-from-urban-kolkata-india
#20
Moytrey Chatterjee, Swagata Ganguly, Pabitra Saha, Subhasish K Guha, Ardhendu Kumar Maji
BACKGROUND: In India, sulphadoxine-pyrimethamine (SP) is now in use as a partner drug of ACT (AS+SP) to treat uncomplicated falciparum malaria since 2010. Declined trend of AS+SP efficacy has been reported from north-eastern states of the country. It is not possible to determine the efficacy of SP alone from any study with ACT. So, this work was designed to study the pattern of polymorphisms in pfdhfr and pfdhps genes to predict the SP resistance status among parasite population of urban Kolkata after five years of ACT implementation...
May 19, 2017: Infection, Genetics and Evolution
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