scholarly journals Comparative Efficacies of Artemisinin Combination Therapies in Plasmodium falciparum Malaria and Polymorphism ofpfATPase6,pfcrt,pfdhfr, andpfdhpsGenes in Tea Gardens of Jalpaiguri District, India

2012 ◽  
Vol 56 (5) ◽  
pp. 2511-2517 ◽  
Author(s):  
Pabitra Saha ◽  
Subhasish K. Guha ◽  
Sonali Das ◽  
Shrabanee Mullick ◽  
Swagata Ganguly ◽  
...  
Keyword(s):  
Plasmodium Falciparum Malaria ◽  
Study Groups ◽  
Combination Therapies ◽  
Antimalarial Drug Resistance ◽  
Content Type ◽  
Private Practitioners ◽  
Mutational Pattern ◽  
Sequencing Method ◽  
Periodic Monitoring ◽  
Artemisinin Combination Therapies

ABSTRACTIn India, chloroquine has been replaced by a combination of artesunate and sulfadoxine-pyrimethamine (AS-SP) for uncomplicatedP. falciparummalaria. Other available combinations, artemether-lumefantrine (AM-LF) and artesunate-mefloquine (AS-MQ), not included in the national program, are widely used by private practitioners. Little is known about the therapeutic efficacy of these artemisinin combinations and the prevalence of molecular markers associated with antimalarial drug resistance. A total of 157 patients withP. falciparummonoinfection were recruited and randomized into three study groups (AS-SP, AM-LF, and AS-MQ). All patients were followed up for 42 days to study the clinical and parasitological responses according to the WHO protocol (2009). We assessed the polymorphism of thepfATPase6,pfcrt,pfdhfr, andpfdhpsgenes by the DNA-sequencing method. The PCR-corrected therapeutic efficacies of AS-SP, AM-LF, and AS-MQ were 90.6% (95% confidence interval [CI], 0.793 to 0.969), 95.9% (95% CI, 0.860 to 0.995), and 100% (95% CI, 0.927 to 1.00), respectively. No specific mutational pattern was observed in thepfATPase6gene. All isolates had a K76T mutation in thepfcrtgene. In thepfdhfr-pfdhpsgenotype, quadruple mutation was frequent, and quintuple mutation was documented in 6.3% ofP. falciparumisolates. The significant failure rate of AS-SP (9.5%), although within the limit (10%) for drug policy change, was due to SP failure because of prevailing mutations inpfdhfr, I51R59N108, withpfdhps, G437and/or E540. The efficacy of this ACT needs periodic monitoring. Artemether-lumefantrine and artesunate-mefloquine are effective alternatives to the artesunate-sulfadoxine-pyrimethamine combination.

scholarly journals Combined Transcriptome and Proteome Profiling for Role of pfEMP1 in Antimalarial Mechanism of Action of Dihydroartemisinin

2021 ◽  
Author(s):  
Lina Chen ◽  
Zhongyuan Zheng ◽  
Hui Liu ◽  
Xi Wang ◽  
Shuiqing Qu ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Mechanism Of Action ◽  
Blood Cells ◽  
Artemisinin Derivative ◽  
Combination Therapies ◽  
Proteomic Profiling ◽  
First Line ◽  
Content Type ◽  
Artemisinin Combination Therapies

Malaria parasites induce morphological and biochemical changes in the membranes of parasite-infected red blood cells (iRBCs) for propagation, with artemisinin combination therapies as the first-line treatments. To understand whether artemisinin targets or interacts with iRBC membrane proteins, this study investigated the molecular changes caused by dihydroartemisinin (DHA), an artemisinin derivative, in Plasmodium falciparum 3D7 using a combined transcriptomic and membrane proteomic profiling approach.

scholarly journals Molecular Surveillance of Drug Resistance of Plasmodium falciparum Isolates Imported from Angola in Henan Province, China

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Ruimin Zhou ◽  
Chengyun Yang ◽  
Suhua Li ◽  
Yuling Zhao ◽  
Ying Liu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Antimalarial Drug ◽  
Henan Province ◽  
Nucleotide Polymorphisms ◽  
Combination Therapies ◽  
Antimalarial Drug Resistance ◽  
Single Nucleotide ◽  
Molecular Surveillance ◽  
Content Type

ABSTRACT Angola was the main origin country for the imported malaria in Henan Province, China. Antimalarial drug resistance has posed a threat to the control and elimination of malaria. Several molecular markers were confirmed to be associated with the antimalarial drug resistance, such as pfcrt, pfmdr1, pfdhfr, pfdhps, and K13. This study evaluated the drug resistance of the 180 imported Plasmodium falciparum isolates from Angola via nested PCR using Sanger sequencing. The prevalences of pfcrt C72V73M74N75K76, pfmdr1 N86Y184S1034N1042D1246, pfdhfr A16N51C59S108D139I164, and pfdhps S436A437A476K540A581 were 69.4%, 59.9%, 1.3% and 6.3%, respectively. Three nonsynonymous (A578S, M579I, and Q613E) and one synonymous (R471R) mutation of K13 were found, the prevalences of which were 2.5% and 1.3%, respectively. The single nucleotide polymorphisms (SNPs) in pfcrt, pfmdr1, pfdhfr, and pfdhps were generally shown as multiple mutations. The mutant prevalence of pfcrt reduced gradually, but pfdhfr and pfdhps still showed high mutant prevalence, while pfmdr1 was relatively low. The mutation of the K13 gene was rare. Molecular surveillance of artemisinin (ART) resistance will be used as a tool to evaluate the real-time efficacy of the artemisinin-based combination therapies (ACTs) and the ART resistance situation.

scholarly journals Efficacy, safety and tolerability of three regimens of artemisinin combination therapy in the management of Plasmodium falciparum malaria: a comparative study

2019 ◽  
Vol 8 (10) ◽  
pp. 2179
Author(s):  
Komal Mallinath Halkai ◽  
Bapugouda Sahebagouda Patil
Keyword(s):  
Plasmodium Falciparum ◽  
Falciparum Malaria ◽  
Artemisinin Combination Therapy ◽  
Plasmodium Falciparum Malaria ◽  
Combination Therapies ◽  
Medical Sciences ◽  
Treatment Groups ◽  
The Mean ◽  
Wbc Count ◽  
Artemisinin Combination Therapies

Background: The WHO now recommends the use of artemisinin-based combination therapies for the first-line treatment of Plasmodium falciparum malaria to reduce the drug resistance. Hence, this study was designed to compare the efficacy, safety and tolerability of three regimens of artemisinin combination therapies in malaria diagnosed patients of Kamineni Institute of Medical Sciences Hospital, Narketpally.Methods: Total of 104 subjects had been allocated to 3 different artemisinin-based combinations regimens in a period of 2 years during December 2013 - November 2015. Out of 104 subjects, 34 received artemisinin-sulphadoxine pyrimethamine regimen, 33 subjects received artemisinin-lumefantrine regimen, and 37 subjects received artemisinin-doxycycline regimen. All the three regimens were studied for their efficacy, safety and tolerability.Results: The mean number of febrile days in artesunate-sulfadoxine pyrimethamine group (3.43±0.92) and artesunate-doxycycline group (3.51± 0.74) were comparatively less than artemether-lumefantrine group (4.33±0.77) which is statistically significant. The mean Hb%, RBC count, WBC count was not significantly different on day 7 in comparison to day 1 in all the three regimens of treatment groups. 14 subjects among the 104 had mild thrombocytopenia which was significantly improved on day 7 in all the three regimens of treatment groups.Conclusions: Artesunate-sulfadoxine-pyrimethamine and artesunate-doxycycline regimens showed better efficacy, safety and tolerability than artemether-lumefantrine regimen.

scholarly journals Little Polymorphism at the K13 Propeller Locus in Worldwide Plasmodium falciparum Populations Prior to the Introduction of Artemisinin Combination Therapies

2016 ◽  
Vol 60 (6) ◽  
pp. 3340-3347 ◽  
Author(s):  
Toshihiro Mita ◽  
Richard Culleton ◽  
Nobuyuki Takahashi ◽  
Masatoshi Nakamura ◽  
Takahiro Tsukahara ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Haplotype Diversity ◽  
Artemisinin Resistance ◽  
Pairwise Comparison ◽  
Purifying Selection ◽  
Parasite Clearance ◽  
Combination Therapies ◽  
Content Type ◽  
Exposed Population ◽  
Artemisinin Combination Therapies

The emergence and spread of artemisinin-resistantPlasmodium falciparumis of huge concern for the global effort toward malaria control and elimination. Artemisinin resistance, defined as a delayed time to parasite clearance following administration of artemisinin, is associated with mutations in thePfkelch13gene of resistant parasites. To date, as many as 60 nonsynonymous mutations have been identified in this gene, but whether these mutations have been selected by artemisinin usage or merely reflect natural polymorphism independent of selection is currently unknown. To clarify this, we sequenced thePfkelch13propeller domain in 581 isolates collected before (420 isolates) and after (161 isolates) the implementation of artemisinin combination therapies (ACTs), from various regions of endemicity worldwide. Nonsynonymous mutations were observed in 1% of parasites isolated prior to the introduction of ACTs. Frequencies of mutant isolates, nucleotide diversity, and haplotype diversity were significantly higher in the parasites isolated from populations exposed to artemisinin than in those from populations that had not been exposed to the drug. In the artemisinin-exposed population, a significant excess of dN compared to dS was observed, suggesting the presence of positive selection. In contrast, pairwise comparison of dN and dS and the McDonald and Kreitman test indicate that purifying selection acts on thePfkelch13propeller domain in populations not exposed to ACTs. These population genetic analyses reveal a low baseline ofPfkelch13polymorphism, probably due to purifying selection in the absence of artemisinin selection. In contrast, variousPfkelch13mutations have been selected under artemisinin pressure.

scholarly journals K13 Propeller Alleles, mdr1 Polymorphism, and Drug Effectiveness at Day 3 after Artemether-Lumefantrine Treatment for Plasmodium falciparum Malaria in Colombia, 2014-2015

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Madeline Montenegro ◽  
Aaron T. Neal ◽  
Maritza Posada ◽  
Briegel De las Salas ◽  
Tatiana M. Lopera-Mesa ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Plasmodium Falciparum Malaria ◽  
Parasite Clearance ◽  
Content Type ◽  
Drug Effectiveness ◽  
Multiple Copies ◽  
Multidrug Resistance 1 Gene ◽  
Mdr1 Polymorphism ◽  
High Treatment ◽  
Artemisinin Combination Therapies

ABSTRACT High treatment failure rates for Plasmodium falciparum malaria have been reported in Colombia for chloroquine, amodiaquine, and sulfadoxine-pyrimethamine. Artemisinin combination therapies were introduced in 2006 in Colombia, where artemether-lumefantrine (AL) is currently used to treat uncomplicated P. falciparum malaria. Artemisinin (ART) resistance was initially observed in Southeast Asia as an increased parasite clearance time, manifesting as a positive thick-blood smear on day 3 after treatment (D3 positivity). Recently, mutations in the propeller domain of the P. falciparum kelch13 gene (K13 propeller) have been associated with ART resistance. In this study, we surveyed AL effectiveness at D3 and molecular markers of drug resistance among 187 uncomplicated P. falciparum cases in 4 regions of Colombia from June 2014 to July 2015. We found that 3.2% (4/125) of patients showed D3 positivity, 100% (163/163) of isolates carried wild-type K13 propeller alleles, 12.9% (23/178) of isolates had multiple copies of the multidrug resistance 1 gene (mdr1), and 75.8% (113/149) of isolates harbored the double mutant NFSDD mdr1 haplotype (the underlining indicates mutant alleles). These data suggest that ART resistance is not currently suspected in Colombia but that monitoring for lumefantrine resistance and AL failures should continue.

scholarly journals In VitroActivities of Primaquine-Schizonticide Combinations on Asexual Blood Stages and Gametocytes of Plasmodium falciparum

2015 ◽  
Vol 59 (12) ◽  
pp. 7650-7656 ◽  
Author(s):  
Mynthia Cabrera ◽  
Liwang Cui
Keyword(s):  
Plasmodium Falciparum ◽  
World Health ◽  
Combination Therapies ◽  
Content Type ◽  
Synergistic Interactions ◽  
Health Organization ◽  
Potential Interactions ◽  
Artemisinin Combination Therapies ◽  
Antagonistic Interactions

ABSTRACTCurrently, the World Health Organization recommends addition of a 0.25-mg base/kg single dose of primaquine (PQ) to artemisinin combination therapies (ACTs) forPlasmodium falciparummalaria as a gametocytocidal agent for reducing transmission. Here, we investigated the potential interactions of PQ with the long-lasting components of the ACT drugs for eliminating the asexual blood stages and gametocytes ofin vitro-culturedP. falciparumstrains. Using the SYBR green I assay for asexual parasites and a flow cytometry-based assay for gametocytes, we determined the interactions of PQ with the schizonticides chloroquine, mefloquine, piperaquine, lumefantrine, and naphthoquine. With the sums of fractional inhibitory concentrations and isobolograms, we were able to determine mostly synergistic interactions for the various PQ and schizonticide combinations on the blood stages ofP. falciparumlaboratory strains. The synergism in inhibiting asexual stages and gametocytes was highly evident with PQ-naphthoquine, whereas synergism was moderate for the PQ-piperaquine, PQ-chloroquine, and PQ-mefloquine combinations. We have detected potentially antagonistic interactions between PQ and lumefantrine under certain drug combination ratios, suggesting that precautions might be needed when PQ is added as the gametocytocide to the artemether-lumefantrine ACT (Coartem).

scholarly journals Artemisinin-Based Antimalarial Drug Therapy: Molecular Pharmacology and Evolving Resistance

2019 ◽  
Vol 4 (2) ◽  
pp. 89 ◽  
Author(s):  
Laura E. Heller ◽  
Paul D. Roepe
Keyword(s):  
Plasmodium Falciparum ◽  
Artemisinin Resistance ◽  
Standard Of Care ◽  
Plasmodium Falciparum Malaria ◽  
Genetic Mutations ◽  
South East Asia ◽  
Molecular Pharmacology ◽  
Combination Therapies ◽  
The World ◽  
Artemisinin Combination Therapies

The molecular pharmacology of artemisinin (ART)-based antimalarial drugs is incompletely understood. Clinically, these drugs are used in combination with longer lasting partner drugs in several different artemisinin combination therapies (ACTs). ACTs are currently the standard of care against Plasmodium falciparum malaria across much of the world. A harbinger of emerging artemisinin resistance (ARTR), known as the delayed clearance phenotype (DCP), has been well documented in South East Asia (SEA) and is beginning to affect the efficacy of some ACTs. Though several genetic mutations have been associated with ARTR/DCP, a molecular mechanism remains elusive. This paper summarizes our current understanding of ART molecular pharmacology and hypotheses for ARTR/DCP.

scholarly journals Changing Molecular Markers of Antimalarial Drug Sensitivity across Uganda

2018 ◽  
Vol 63 (3) ◽  
Author(s):  
Victor Asua ◽  
Joanna Vinden ◽  
Melissa D. Conrad ◽  
Jennifer Legac ◽  
Simon P. Kigozi ◽  
...  
Keyword(s):  
Antimalarial Drug ◽  
Drug Sensitivity ◽  
Artemisinin Resistance ◽  
Wild Type ◽  
National Treatment ◽  
Antimalarial Drug Resistance ◽  
Content Type ◽  
Increased Sensitivity ◽  
Low Prevalence ◽  
Poor Efficacy

ABSTRACT The potential spread of antimalarial drug resistance to Africa, in particular for artemisinins and key partner drugs, is a major concern. We surveyed Plasmodium falciparum genetic markers associated with drug sensitivity on 3 occasions at ∼6-month intervals in 2016 and 2017 at 10 sites representing a range of epidemiological settings in Uganda. For putative drug transporters, we found continued evolution toward wild-type sequences associated with increased sensitivity to chloroquine. For pfcrt K76T, by 2017 the prevalence of the wild type was >60% at all sites and >90% at 6 sites. For the pfmdr1 N86Y and D1246Y alleles, wild type prevalence ranged from 80 to 100%. We found low prevalence of K13 propeller domain mutations, which are associated with artemisinin resistance in Asia, but one mutation previously identified in northern Uganda, 675V, was seen in 2.0% of samples, including 5.5% of those from the 3 northernmost sites. Amplification of the pfmdr1 and plasmepsin2 genes, associated elsewhere with decreased sensitivity to lumefantrine and piperaquine, respectively, was seen in <1% of samples. For the antifolate targets pfdhfr and pfdhps, 5 mutations previously associated with resistance were very common, and the pfdhfr 164L and pfdhps 581G mutations associated with higher-level resistance were seen at multiple sites, although prevalence did not clearly increase over time. Overall, changes were consistent with the selective pressure of the national treatment regimen, artemether-lumefantrine, with increased sensitivity to chloroquine, and with poor efficacy of antifolates. Strong evidence for resistance to artemisinins was not seen. Continued surveillance of markers that predict antimalarial drug sensitivity is warranted.

scholarly journals Clinical Evaluation of the iCubate iC-GPC Assay for Detection of Gram-Positive Bacteria and Resistance Markers from Positive Blood Cultures

2018 ◽  
Vol 56 (9) ◽  
Author(s):  
Paul A. Granato ◽  
Melissa M. Unz ◽  
Raymond H. Widen ◽  
Suzane Silbert ◽  
Stephen Young ◽  
...  
Keyword(s):  
Blood Culture ◽  
Staphylococcus Epidermidis ◽  
Bloodstream Infections ◽  
Blood Cultures ◽  
Gram Positive ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Sequencing Method ◽  
Resistance Markers ◽  
Gram Positive Cocci

ABSTRACT The iC-GPC Assay (iCubate, Huntsville, AL) is a qualitative multiplex test for the detection of five of the most common Gram-positive bacteria (Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Enterococcus faecalis, and Enterococcus faecium) responsible for bacterial bloodstream infections, performed directly from positive blood cultures. The assay also detects the presence of the mecA, vanA, and vanB resistance determinants. This study comparatively evaluated the performance of the iC-GPC Assay against the Verigene Gram-positive blood culture (BC-GP) assay (Luminex Corp., Austin, TX) for 1,134 patient blood culture specimens positive for Gram-positive cocci. The iC-GPC Assay had an overall percent agreement with the BC-GP assay of 95.5%. Discordant specimens were further analyzed by PCR and a bidirectional sequencing method. The results indicate that the iC-GPC Assay together with the iCubate system is an accurate and reliable tool for the detection of the five most common Gram-positive bacteria and their resistance markers responsible for bloodstream infections.

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