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Steven R. Meshnick - One of the best experts on this subject based on the ideXlab platform.

  • Recent highlights in Antimalarial Drug Resistance and chemotherapy research.
    Trends in parasitology, 2008
    Co-Authors: David A. Fidock, Richard T. Eastman, Stephen A. Ward, Steven R. Meshnick
    Abstract:

    This review summarizes recent investigations into Antimalarial Drug Resistance and chemotherapy, including reports of some of the many exciting talks and posters on this topic that were presented at the third Molecular Approaches to Malaria meeting held in Lorne, Australia, in February 2008 (MAM 2008). After surveying this area of research, we focus on two important questions: what is the molecular contribution of pfcrt to chloroquine Resistance, and what is the mechanism of action of artemisinin? We conclude with thoughts about the current state of Antimalarial chemotherapy and priorities moving forward.

  • Real-time PCR methods for monitoring Antimalarial Drug Resistance
    Trends in parasitology, 2005
    Co-Authors: Paul E. Wilson, Alisa P. Alker, Steven R. Meshnick
    Abstract:

    Drug-resistant Plasmodium falciparum is a challenge to malaria control programs. Policy makers currently depend on in vivo (and, sometimes, in vitro ) Resistance testing to set treatment guidelines. Molecular markers such as mutations in dhfr , dhps , pfcrt and pfmdr1 represent potential surveillance tools. In this article, we describe newer high-throughput methods for detecting these molecular markers. One method, 5′ nuclease real-time polymerase chain reaction, is discussed in detail.

Georgina S. Humphreys - One of the best experts on this subject based on the ideXlab platform.

  • An online mapping database of molecular markers of Drug Resistance in Plasmodium falciparum: the ACT Partner Drug Molecular Surveyor.
    Malaria journal, 2019
    Co-Authors: Sabina Dahlström Otienoburu, Anders Björkman, Ignacio Suay, Steven Garcia, Nigel V. Thomas, Suttipat Srisutham, Georgina S. Humphreys
    Abstract:

    Background Prior to this project, only a handful of online visualizations existed for exploring the published literature on molecular markers of Antimalarial Drug Resistance, and none specifically for the markers associated with Plasmodium falciparum Resistance to the partner Drugs in artemisinin-based combination therapy (ACT). Molecular information is collected in studies with different designs, using a variety of molecular methodologies and data analysis strategies, making it difficult to compare across studies. The purpose of this project was to develop a free online tool, which visualizes the widely published data on molecular markers of Antimalarial Drug Resistance, starting with the two genes pfcrt and pfmdr-1, associated with Resistance to the three most common partner Drugs; amodiaquine, lumefantrine and mefloquine.

  • Diagnostic accuracy of molecular methods for detecting markers of Antimalarial Drug Resistance in clinical samples of Plasmodium falciparum: protocol for an update to a systematic review and meta-analysis.
    Systematic reviews, 2018
    Co-Authors: Rebekah Burrow, Thomas R. Fanshawe, Georgina S. Humphreys
    Abstract:

    Each year, infection with Plasmodium causes millions of clinical cases of malaria and hundreds of thousands of deaths. Resistance to different Antimalarial medications continues to develop and spread, threatening effective prophylaxis and treatment. Surveillance of Resistance is required to inform health policy and preserve effective Antimalarial Drugs; molecular methods can be used to surveil likely parasite Resistances. However, there is no consensus on the most accurate molecular methods, and large variation exists in practice. The objective of this update to this systematic review is to improve and update identification of the sensitivity and specificity of each molecular method for detecting selected Antimalarial Drug Resistance markers. We will include diagnostic accuracy studies that compare at least two of any molecular methods to examine blood samples from patients diagnosed with, or suspected of having malaria, to detect at least one selected marker of Antimalarial Drug Resistance. We will search PubMed, EMBASE, BIOSIS, and Web of Science from 2000 to present. Two reviewers will independently screen all results, extract data, consider applicability, and evaluate the methodological quality of included studies using QUADAS-2. We will carry out a meta-analysis and use statistical methods to compare results from homogenous studies. We will use narrative to synthesise and compare results of heterogeneous studies. This review will help to identify sub-optimal molecular methods for Antimalarial marker detection which may be discontinued and identify more sensitive and specific methods which may be adopted. More sensitive and specific detection of Drug Resistance can be used to improve the breadth and accuracy of surveillance. This would enable the identification of previously undiscovered areas of Antimalarial Resistances and susceptibilities, improve the precision of estimates of the prevalence of Resistances, and improve our ability to detect smaller changes in these patterns. Higher-quality evidence generated by more accurate and detailed surveillance can be used to inform guidelines on the use of Antimalarial Drugs, leading to better outcomes for more patients. This systematic review protocol was registered with PROSPERO on 22 November 2017 (registration number CRD42017082101 ).

  • Diagnostic accuracy of molecular methods for detecting markers of Antimalarial Drug Resistance in clinical samples of Plasmodium falciparum: Protocol for an update to a systematic review and meta-analysis 11 Medical and Health Sciences 1117 Public He
    Systematic Reviews, 2018
    Co-Authors: Rebekah Burrow, Thomas R. Fanshawe, Georgina S. Humphreys
    Abstract:

    © 2018 The Author(s). Background: Each year, infection with Plasmodium causes millions of clinical cases of malaria and hundreds of thousands of deaths. Resistance to different Antimalarial medications continues to develop and spread, threatening effective prophylaxis and treatment. Surveillance of Resistance is required to inform health policy and preserve effective Antimalarial Drugs; molecular methods can be used to surveil likely parasite Resistances. However, there is no consensus on the most accurate molecular methods, and large variation exists in practice. The objective of this update to this systematic review is to improve and update identification of the sensitivity and specificity of each molecular method for detecting selected Antimalarial Drug Resistance markers. Methods: We will include diagnostic accuracy studies that compare at least two of any molecular methods to examine blood samples from patients diagnosed with, or suspected of having malaria, to detect at least one selected marker of Antimalarial Drug Resistance. We will search PubMed, EMBASE, BIOSIS, and Web of Science from 2000 to present. Two reviewers will independently screen all results, extract data, consider applicability, and evaluate the methodological quality of included studies using QUADAS-2. We will carry out a meta-analysis and use statistical methods to compare results from homogenous studies. We will use narrative to synthesise and compare results of heterogeneous studies. Discussion: This review will help to identify sub-optimal molecular methods for Antimalarial marker detection which may be discontinued and identify more sensitive and specific methods which may be adopted. More sensitive and specific detection of Drug Resistance can be used to improve the breadth and accuracy of surveillance. This would enable the identification of previously undiscovered areas of Antimalarial Resistances and susceptibilities, improve the precision of estimates of the prevalence of Resistances, and improve our ability to detect smaller changes in these patterns. Higher-quality evidence generated by more accurate and detailed surveillance can be used to inform guidelines on the use of Antimalarial Drugs, leading to better outcomes for more patients. Systematic review registration: This systematic review protocol was registered with PROSPERO on 22 November 2017 (registration number CRD42017082101).

N. J. White - One of the best experts on this subject based on the ideXlab platform.

  • The threat of Antimalarial Drug Resistance
    Tropical diseases travel medicine and vaccines, 2016
    Co-Authors: Borimas Hanboonkunupakarn, N. J. White
    Abstract:

    The battle between man and malaria has continued for thousands of years. Antimalarial Drugs are essential weapons to fight the disease, but their efficacy is threatened by Drug Resistance which continues to emerge creating a major obstacle to malaria control and jeopardizing renewed hopes for elimination. As 2016 is the first year under WHO Global Technical Strategy for Malaria 2016–2030, it is a good time to ponder the progress of both sides and plan for the future.

  • Pharmacokinetic Determinants of the Window of Selection for Antimalarial Drug Resistance
    Antimicrobial agents and chemotherapy, 2008
    Co-Authors: Kasia Stepniewska, N. J. White
    Abstract:

    The selection and spread of Antimalarial Drug Resistance pose enormous challenges to the health of people living in tropical countries. Most Antimalarial Drugs are slowly eliminated and so, following treatment in areas of endemicity, provide a gradient of concentrations to which newly acquired parasites are exposed. There is a variable period during which a new blood-stage infection with resistant malaria parasites can emerge from the liver and subsequently produce gametocyte densities sufficient for transmission while reinfection by sensitive parasites is still suppressed. This “window of selection” drives the spread of Resistance. We have examined the factors which determine the duration of this window and, thus, the Resistance selection pressure. The duration ranges from zero to several months and is dependent on the degree of parasite Resistance, the slope of the concentration-effect relationship, and the elimination kinetics of the Antimalarial Drug. The time at which the window opens and the duration of opening are both linear functions of the terminal elimination half-life. Because of competition from sibling susceptible parasites, the greater risks of extinction with low starting numbers, and opening of the window only when blood concentrations have fallen below the MIC, the window of selection for de novo Resistance is narrower than that for Resistance acquired elsewhere. The windows were examined for the currently available Antimalarials. Drugs with elimination half-lives of less than 1 day, such as the artemisinins and quinine, do not select for Resistance during the elimination phase.

  • How Antimalarial Drug Resistance affects post-treatment prophylaxis
    Malaria journal, 2008
    Co-Authors: N. J. White
    Abstract:

    Slowly eliminated Antimalarial Drugs suppress malaria reinfections for a period of time determined by the dose, the pharmacokinetic properties of the Drug, and the susceptibility of the infecting parasites. This effect is called post-treatment prophylaxis (PTP). The clinical benefits of preventing recrudescence (reflecting treatment efficacy) compared with preventing reinfection (reflecting PTP) need further assessment. Antimalarial Drug Resistance shortens PTP. While blood concentrations are in the terminal elimination phase, the degree of shortening may be estimated from measurements of in-vitro susceptibility and the terminal elimination half-life. More information is needed on PTP following intermittent preventive treatments, and on the relationship between the duration of PTP and immunity, so that policy recommendations can have a firmer evidence base.

  • Antimalarial Drug Resistance
    J.Clin.Invest, 2004
    Co-Authors: N. J. White
    Abstract:

    Malaria, the most prevalent and most pernicious parasitic disease of humans, is estimated to kill between one and two million people, mainly children, each year. Resistance has emerged to all classes of Antimalarial Drugs except the artemisinins and is responsible for a recent increase in malaria-related mortality, particularly in Africa. The de novo emergence of Resistance can be prevented by the use of Antimalarial Drug combinations. Artemisinin-derivative combinations are particularly effective, since they act rapidly and are well tolerated and highly effective. Widespread use of these Drugs could roll back malaria

  • delaying Antimalarial Drug Resistance with combination chemotherapy
    Parassitologia, 1999
    Co-Authors: N. J. White
    Abstract:

    Abstract Resistance to Antimalarial Drugs arises when spontaneously occurring mutants with gene mutations or amplifications which confer reduced Drug susceptibility are selected, and are then transmitted. Simultaneous use of two or more Antimalarials with different modes of action and which therefore do not share the same Resistance mechanisms will reduce the chance of selection, because the chance of a resistant mutant surviving is the product of the parasite mutation rates for the individual Drugs, multiplied by the number of parasites in an infection that are exposed to the Drugs. The artemisinin derivatives are very active Antimalarials, which produce large reductions in parasite biomass per asexual cycle, and reduce malaria transmissibility. To date no Resistance to these Drugs has been reported. These Drugs therefore make particularly effective combination partners. This suggests that Antimalarial Drugs should not be used alone in treatment, but always in combination, as in the treatment of tuberculosis or HIV, and that the combination should include artemisinin or one of its derivatives.

Abdelrahim Osman Mohamed - One of the best experts on this subject based on the ideXlab platform.

  • Antimalarial Drug Resistance molecular makers of Plasmodium falciparum isolates from Sudan during 2015–2017
    PloS one, 2020
    Co-Authors: Maazza Hussien, Muzamil Mahdi Abdel Hamid, Elamin Abdelkarim Elamin, Abdalla O. Hassan, Arwa H. Elaagip, Abusofyan Hamattallah A. Salama, Mohammed H. Abdelraheem, Abdelrahim Osman Mohamed
    Abstract:

    Background Current malaria control and elimination strategies rely mainly on efficacious Antimalarial Drugs. However, Drug Resistance is a major threat facing malaria control programs. Determination of Drug Resistance molecular markers is useful in the monitoring and surveillance of malaria Drug efficacy. This study aimed to determine the mutations and haplotypes frequencies of different genes linked with Antimalarial Drug Resistance in certain areas in Sudan. Methods A total of 226 dried blood spots (DBS) of microscopically diagnosed P. falciparum isolates were collected from Khartoum and three other areas in Sudan during 2015–2017. Plasmodium falciparum confirmation and multiplicity of infection was assessed using the Sanger’s 101 SNPs-barcode and speciation was confirmed using regions of the parasite mitochondria. Molecular genotyping of Drug Resistance genes (Pfcrt, Pfmdr1, Pfdhfr, Pfdhps, exonuclease, Pfk13, parasite genetic background (PGB) (Pfarps10, ferredoxin, Pfcrt, Pfmdr2)) was also performed. All genotypes were generated by selective regions amplicon sequencing of the parasite genome using the Illumina MiSeq platform at the Wellcome Sanger Institute, UK then genotypes were translated into Drug Resistance haplotypes and species determination. Findings In total 225 samples were confirmed to be P. falciparum. A higher proportion of multiplicity of infection was observed in Gezira (P

  • Antimalarial Drug Resistance molecular makers of plasmodium falciparum isolates from sudan during 2015 2017
    PLOS ONE, 2020
    Co-Authors: Maazza Hussien, Muzamil Mahdi Abdel Hamid, Elamin Abdelkarim Elamin, Abdalla O. Hassan, Arwa H. Elaagip, Abusofyan Hamattallah A. Salama, Mohammed H. Abdelraheem, Abdelrahim Osman Mohamed
    Abstract:

    Background Current malaria control and elimination strategies rely mainly on efficacious Antimalarial Drugs. However, Drug Resistance is a major threat facing malaria control programs. Determination of Drug Resistance molecular markers is useful in the monitoring and surveillance of malaria Drug efficacy. This study aimed to determine the mutations and haplotypes frequencies of different genes linked with Antimalarial Drug Resistance in certain areas in Sudan. Methods A total of 226 dried blood spots (DBS) of microscopically diagnosed P. falciparum isolates were collected from Khartoum and three other areas in Sudan during 2015–2017. Plasmodium falciparum confirmation and multiplicity of infection was assessed using the Sanger’s 101 SNPs-barcode and speciation was confirmed using regions of the parasite mitochondria. Molecular genotyping of Drug Resistance genes (Pfcrt, Pfmdr1, Pfdhfr, Pfdhps, exonuclease, Pfk13, parasite genetic background (PGB) (Pfarps10, ferredoxin, Pfcrt, Pfmdr2)) was also performed. All genotypes were generated by selective regions amplicon sequencing of the parasite genome using the Illumina MiSeq platform at the Wellcome Sanger Institute, UK then genotypes were translated into Drug Resistance haplotypes and species determination. Findings In total 225 samples were confirmed to be P. falciparum. A higher proportion of multiplicity of infection was observed in Gezira (P<0.001) based on the Sanger 101 SNPs -barcode. The overall frequency of mutant haplotype Pfcrt 72–76 CVIET was 71.8%. For Pfmdr1, N86Y was detected in 53.6%, Y184F was observed in 88.1% and D1246Y was detected in 1.5% of the samples. The most frequently observed haplotype was YFD 47.4%. For Pfdhfr (codons 51, 59,108,164), the ICNI haplotype was the most frequent (80.7%) while for Pfdhps (codons 436, 437, 540, 581, 613) the (SGEAA) was most frequent haplotype (41%). The Quadruple mutation (dhfr N51I, S108N + dhps A437G, K540E) was the highest frequent combined mutation (33.9%). In Pfkelch13 gene, 18 non‐synonymous mutations were detected, 7 of them were detected in other African countries. The most frequent Pfk13 mutation was E433D detected in four samples. All of the Pfk13 mutant alleles have not been reported to belong to mutations associated with delayed parasite clearance in Southeast Asia. PGB mutations were detected only in Pfcrt N326S\I (46.3%) and Pfcrt I356T (8.2%). The exonuclease mutation was not detected. There was no significant variation in mutant haplotypes between study areas. Conclusions There was high frequency of mutations in Pfcrt, Pfdhfr and Pfdhps in this study. These mutations are associated with chloroquine and sulfadoxine-pyrimethamine (SP) Resistance. Many SNPs in Pfk13 not linked with delayed parasite clearance were observed. The exonuclease E415G mutation which is linked with piperaquine Resistance was not reported.

Maazza Hussien - One of the best experts on this subject based on the ideXlab platform.

  • Antimalarial Drug Resistance molecular makers of Plasmodium falciparum isolates from Sudan during 2015–2017
    PloS one, 2020
    Co-Authors: Maazza Hussien, Muzamil Mahdi Abdel Hamid, Elamin Abdelkarim Elamin, Abdalla O. Hassan, Arwa H. Elaagip, Abusofyan Hamattallah A. Salama, Mohammed H. Abdelraheem, Abdelrahim Osman Mohamed
    Abstract:

    Background Current malaria control and elimination strategies rely mainly on efficacious Antimalarial Drugs. However, Drug Resistance is a major threat facing malaria control programs. Determination of Drug Resistance molecular markers is useful in the monitoring and surveillance of malaria Drug efficacy. This study aimed to determine the mutations and haplotypes frequencies of different genes linked with Antimalarial Drug Resistance in certain areas in Sudan. Methods A total of 226 dried blood spots (DBS) of microscopically diagnosed P. falciparum isolates were collected from Khartoum and three other areas in Sudan during 2015–2017. Plasmodium falciparum confirmation and multiplicity of infection was assessed using the Sanger’s 101 SNPs-barcode and speciation was confirmed using regions of the parasite mitochondria. Molecular genotyping of Drug Resistance genes (Pfcrt, Pfmdr1, Pfdhfr, Pfdhps, exonuclease, Pfk13, parasite genetic background (PGB) (Pfarps10, ferredoxin, Pfcrt, Pfmdr2)) was also performed. All genotypes were generated by selective regions amplicon sequencing of the parasite genome using the Illumina MiSeq platform at the Wellcome Sanger Institute, UK then genotypes were translated into Drug Resistance haplotypes and species determination. Findings In total 225 samples were confirmed to be P. falciparum. A higher proportion of multiplicity of infection was observed in Gezira (P

  • Antimalarial Drug Resistance molecular makers of plasmodium falciparum isolates from sudan during 2015 2017
    PLOS ONE, 2020
    Co-Authors: Maazza Hussien, Muzamil Mahdi Abdel Hamid, Elamin Abdelkarim Elamin, Abdalla O. Hassan, Arwa H. Elaagip, Abusofyan Hamattallah A. Salama, Mohammed H. Abdelraheem, Abdelrahim Osman Mohamed
    Abstract:

    Background Current malaria control and elimination strategies rely mainly on efficacious Antimalarial Drugs. However, Drug Resistance is a major threat facing malaria control programs. Determination of Drug Resistance molecular markers is useful in the monitoring and surveillance of malaria Drug efficacy. This study aimed to determine the mutations and haplotypes frequencies of different genes linked with Antimalarial Drug Resistance in certain areas in Sudan. Methods A total of 226 dried blood spots (DBS) of microscopically diagnosed P. falciparum isolates were collected from Khartoum and three other areas in Sudan during 2015–2017. Plasmodium falciparum confirmation and multiplicity of infection was assessed using the Sanger’s 101 SNPs-barcode and speciation was confirmed using regions of the parasite mitochondria. Molecular genotyping of Drug Resistance genes (Pfcrt, Pfmdr1, Pfdhfr, Pfdhps, exonuclease, Pfk13, parasite genetic background (PGB) (Pfarps10, ferredoxin, Pfcrt, Pfmdr2)) was also performed. All genotypes were generated by selective regions amplicon sequencing of the parasite genome using the Illumina MiSeq platform at the Wellcome Sanger Institute, UK then genotypes were translated into Drug Resistance haplotypes and species determination. Findings In total 225 samples were confirmed to be P. falciparum. A higher proportion of multiplicity of infection was observed in Gezira (P<0.001) based on the Sanger 101 SNPs -barcode. The overall frequency of mutant haplotype Pfcrt 72–76 CVIET was 71.8%. For Pfmdr1, N86Y was detected in 53.6%, Y184F was observed in 88.1% and D1246Y was detected in 1.5% of the samples. The most frequently observed haplotype was YFD 47.4%. For Pfdhfr (codons 51, 59,108,164), the ICNI haplotype was the most frequent (80.7%) while for Pfdhps (codons 436, 437, 540, 581, 613) the (SGEAA) was most frequent haplotype (41%). The Quadruple mutation (dhfr N51I, S108N + dhps A437G, K540E) was the highest frequent combined mutation (33.9%). In Pfkelch13 gene, 18 non‐synonymous mutations were detected, 7 of them were detected in other African countries. The most frequent Pfk13 mutation was E433D detected in four samples. All of the Pfk13 mutant alleles have not been reported to belong to mutations associated with delayed parasite clearance in Southeast Asia. PGB mutations were detected only in Pfcrt N326S\I (46.3%) and Pfcrt I356T (8.2%). The exonuclease mutation was not detected. There was no significant variation in mutant haplotypes between study areas. Conclusions There was high frequency of mutations in Pfcrt, Pfdhfr and Pfdhps in this study. These mutations are associated with chloroquine and sulfadoxine-pyrimethamine (SP) Resistance. Many SNPs in Pfk13 not linked with delayed parasite clearance were observed. The exonuclease E415G mutation which is linked with piperaquine Resistance was not reported.