scholarly journals ComparativeEx VivoActivity of Novel Endoperoxides in Multidrug-Resistant Plasmodium falciparum and P. vivax

2012 ◽  
Vol 56 (10) ◽  
pp. 5258-5263 ◽  
Author(s):  
Jutta Marfurt ◽  
Ferryanto Chalfein ◽  
Pak Prayoga ◽  
Frans Wabiser ◽  
Grennady Wirjanata ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Ex Vivo ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Intrinsic Activity ◽  
Drug Resistant ◽  
The Novel ◽  
Content Type ◽  
Artemisinin Derivatives

ABSTRACTThe declining efficacy of artemisinin derivatives againstPlasmodium falciparumhighlights the urgent need to identify alternative highly potent compounds for the treatment of malaria. In Papua Indonesia, where multidrug resistance has been documented against bothP. falciparumandP. vivaxmalaria, comparativeex vivoantimalarial activity againstPlasmodiumisolates was assessed for the artemisinin derivatives artesunate (AS) and dihydroartemisinin (DHA), the synthetic peroxides OZ277 and OZ439, the semisynthetic 10-alkylaminoartemisinin derivatives artemisone and artemiside, and the conventional antimalarial drugs chloroquine (CQ), amodiaquine (AQ), and piperaquine (PIP).Ex vivodrug susceptibility was assessed in 46 field isolates (25P. falciparumand 21P. vivax). The novel endoperoxide compounds exhibited potentex vivoactivity against both species, but significant differences in intrinsic activity were observed. Compared to AS and its active metabolite DHA, all the novel compounds showed lower or equal 50% inhibitory concentrations (IC50s) in both species (median IC50s between 1.9 and 3.6 nM inP. falciparumand 0.7 and 4.6 nM inP. vivax). The antiplasmodial activity of novel endoperoxides showed different cross-susceptibility patterns in the twoPlasmodiumspecies: whereas theirex vivoactivity correlated positively with CQ, PIP, AS, and DHA inP. falciparum, the same was not apparent inP. vivax. The current study demonstrates for the first time potent activity of novel endoperoxides against drug-resistantP. vivax. The high activity against drug-resistant strains of bothPlasmodiumspecies confirms these compounds to be promising candidates for future artemisinin-based combination therapy (ACT) regimens in regions of coendemicity.

scholarly journals Plasmodium falciparum-Based Bioassay for Measurement of Artemisinin Derivatives in Plasma or Serum

2004 ◽  
Vol 48 (3) ◽  
pp. 954-960 ◽  
Author(s):  
Paktiya Teja-Isavadharm ◽  
James O. Peggins ◽  
Thomas G. Brewer ◽  
Nicholas J. White ◽  
H. Kyle Webster ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
High Performance ◽  
Antimalarial Activity ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Response Curves ◽  
Artemisinin Derivatives ◽  
Treatment Regimens ◽  
Limit Of Quantitation

ABSTRACT Artemisinin and its derivatives, artesunate and artemether, are rapidly acting antimalarials that are used for the treatment of severe and uncomplicated multidrug-resistant falciparum malaria. To optimize treatment regimens that use this new class of antimalarials, there is a need for readily available and reproducible assays to monitor drug levels closely in patients. A sensitive and reproducible bioassay for the measurement of the concentrations of artemisinin derivatives in plasma and serum is described. By modifying the in vitro drug susceptibility test, it was found that antimalarial activity in plasma or serum containing an unknown concentration of drug could be equated to the known concentrations of dihydroartemisinin (DHA) required to inhibit parasite growth. Dose-response curves for a Plasmodium falciparum clone (clone W2) and DHA were used as a standard for each assay. Assays with plasma or serum spiked with DHA proved to be reproducible (coefficient of variation, ≤10.9%), with a lower limit of quantitation equivalent to 2.5 ng of DHA per ml. For plasma spiked with artesunate or artemether, there was good agreement of the results obtained by the bioassay and the concentrations measured by high-performance liquid chromatography (HPLC) with electrochemical detection. The bioassay for measurement of the antimalarial activities of artemisinin derivatives in body fluids requires a smaller volume of plasma or serum and is more sensitive than the presently available HPLC methods, can provide pharmacodynamic parameters for determination of activity against the parasite, and should enhance the design of more appropriate dosage regimens for artemisinin drugs.

scholarly journals The Spiroindolone KAE609 Does Not Induce Dormant Ring Stages in Plasmodium falciparum Parasites

2016 ◽  
Vol 60 (9) ◽  
pp. 5167-5174 ◽  
Author(s):  
Marina Chavchich ◽  
Karin Van Breda ◽  
Kerryn Rowcliffe ◽  
Thierry T. Diagana ◽  
Michael D. Edstein
Keyword(s):  
Plasmodium Falciparum ◽  
Growth Arrest ◽  
Artemisinin Resistance ◽  
Multidrug Resistant ◽  
The Novel ◽  
Ring Stage ◽  
Content Type ◽  
Artemisinin Derivatives ◽  
Temporary Growth

ABSTRACTIn vitrodrug treatment with artemisinin derivatives, such as dihydroartemisinin (DHA), results in a temporary growth arrest (i.e., dormancy) at an early ring stage inPlasmodium falciparum. This response has been proposed to play a role in the recrudescence ofP. falciparuminfections following monotherapy with artesunate and may contribute to the development of artemisinin resistance inP. falciparummalaria. We demonstrate here that artemether does induce dormant rings, a finding which further supports the class effect of artemisinin derivatives in inducing the temporary growth arrest ofP. falciparumparasites. In contrast and similarly to lumefantrine, the novel and fast-acting spiroindolone compound KAE609 does not induce growth arrest at the early ring stage ofP. falciparumand prevents the recrudescence of DHA-arrested rings at a low concentration (50 nM). Our findings, together with previous clinical data showing that KAE609 is active against artemisinin-resistant K13 mutant parasites, suggest that KAE609 could be an effective partner drug with a broad range of antimalarials, including artemisinin derivatives, in the treatment of multidrug-resistantP. falciparummalaria.

scholarly journals Ex VivoDrug Susceptibility Testing and Molecular Profiling of Clinical Plasmodium falciparum Isolates from Cambodia from 2008 to 2013 Suggest Emerging Piperaquine Resistance

2015 ◽  
Vol 59 (8) ◽  
pp. 4631-4643 ◽  
Author(s):  
Suwanna Chaorattanakawee ◽  
David L. Saunders ◽  
Darapiseth Sea ◽  
Nitima Chanarat ◽  
Kritsanai Yingyuen ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Ex Vivo ◽  
Artemisinin Combination Therapy ◽  
Artemisinin Resistance ◽  
Drug Susceptibility ◽  
Chloroquine Resistance ◽  
First Line ◽  
Content Type

ABSTRACTCambodia's first-line artemisinin combination therapy, dihydroartemisinin-piperaquine (DHA-PPQ), is no longer sufficiently curative against multidrug-resistantPlasmodium falciparummalaria at some Thai-Cambodian border regions. We report recent (2008 to 2013) drug resistance trends in 753 isolates from northern, western, and southern Cambodia by surveying forex vivodrug susceptibility and molecular drug resistance markers to guide the selection of an effective alternative to DHA-PPQ. Over the last 3 study years, PPQ susceptibility declined dramatically (geomean 50% inhibitory concentration [IC50] increased from 12.8 to 29.6 nM), while mefloquine (MQ) sensitivity doubled (67.1 to 26 nM) in northern Cambodia. These changes in drug susceptibility were significantly associated with a decreased prevalence ofP. falciparummultidrug resistance 1 gene (Pfmdr1) multiple copy isolates and coincided with the timing of replacing artesunate-mefloquine (AS-MQ) with DHA-PPQ as the first-line therapy. Widespread chloroquine resistance was suggested by all isolates being of theP. falciparumchloroquine resistance transporter gene CVIET haplotype. Nearly all isolates collected from the most recent years hadP. falciparumkelch13mutations, indicative of artemisinin resistance.Ex vivobioassay measurements of antimalarial activity in plasma indicated 20% of patients recently took antimalarials, and their plasma had activity (median of 49.8 nM DHA equivalents) suggestive of substantialin vivodrug pressure. Overall, our findings suggest DHA-PPQ failures are associated with emerging PPQ resistance in a background of artemisinin resistance. The observed connection between drug policy changes and significant reduction in PPQ susceptibility with mitigation of MQ resistance supports reintroduction of AS-MQ, in conjunction with monitoring of theP. falciparummdr1copy number, as a stop-gap measure in areas of DHA-PPQ failure.

scholarly journals PotentEx VivoActivity of Naphthoquine and Methylene Blue against Drug-Resistant Clinical Isolates of Plasmodium falciparum and Plasmodium vivax

2015 ◽  
Vol 59 (10) ◽  
pp. 6117-6124 ◽  
Author(s):  
Grennady Wirjanata ◽  
Boni F. Sebayang ◽  
Ferryanto Chalfein ◽  
Prayoga ◽  
Irene Handayuni ◽  
...  
Keyword(s):  
Methylene Blue ◽  
Plasmodium Falciparum ◽  
Ex Vivo ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Trophozoite Stage ◽  
Content Type ◽  
Susceptibility Data ◽  
Highly Active

ABSTRACTThe 4-aminoquinoline naphthoquine (NQ) and the thiazine dye methylene blue (MB) have potentin vitroefficacies againstPlasmodium falciparum, but susceptibility data forP. vivaxare limited. The species- and stage-specificex vivoactivities of NQ and MB were assessed using a modified schizont maturation assay on clinical field isolates from Papua, Indonesia, where multidrug-resistantP. falciparumandP. vivaxare prevalent. Both compounds were highly active againstP. falciparum(median [range] 50% inhibitory concentration [IC50]: NQ, 8.0 nM [2.6 to 71.8 nM]; and MB, 1.6 nM [0.2 to 7.0 nM]) andP. vivax(NQ, 7.8 nM [1.5 to 34.2 nM]; and MB, 1.2 nM [0.4 to 4.3 nM]). Stage-specific drug susceptibility assays revealed significantly greater IC50s in parasites exposed at the trophozoite stage than at the ring stage for NQ inP. falciparum(26.5 versus 5.1 nM,P= 0.021) andP. vivax(341.6 versus 6.5 nM,P= 0.021) and for MB inP. vivax(10.1 versus 1.6 nM,P= 0.010). The excellentex vivoactivities of NQ and MB against bothP. falciparumandP. vivaxhighlight their potential utility for the treatment of multidrug-resistant malaria in areas where both species are endemic.

scholarly journals Ex VivoDrug Susceptibility of Ferroquine against Chloroquine-Resistant Isolates of Plasmodium falciparum and P. vivax

2011 ◽  
Vol 55 (9) ◽  
pp. 4461-4464 ◽  
Author(s):  
Jutta Marfurt ◽  
Ferryanto Chalfein ◽  
Pak Prayoga ◽  
Frans Wabiser ◽  
Enny Kenangalem ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Combination Therapy ◽  
Drug Class ◽  
Ex Vivo ◽  
Multidrug Resistant ◽  
Drug Action ◽  
Drug Uptake ◽  
Content Type ◽  
Excellent Activity

ABSTRACTFerroquine (FQ; SSR97193), a ferrocene-containing 4-aminoquinoline derivate, has potentin vitroefficacy against chloroquine (CQ)-resistantPlasmodium falciparumand CQ-sensitiveP. vivax. In the current study,ex vivoFQ activity was tested in multidrug-resistantP. falciparumandP. vivaxfield isolates using a schizont maturation assay. Although FQ showed excellent activity against CQ-sensitive and -resistantP. falciparumandP. vivax(median 50% inhibitory concentrations [IC50s], 9.6 nM and 18.8 nM, respectively), there was significant cross-susceptibility with the quinoline-based drugs chloroquine, amodiaquine, and piperaquine (forP. falciparum,r= 0.546 to 0.700,P< 0.001; forP. vivax,r= 0.677 to 0.821,P< 0.001). The observedex vivocross-susceptibility is likely to reflect similar mechanisms of drug uptake/efflux and modes of drug action of this drug class. However, the potent activity of FQ against resistant isolates of bothP. falciparumandP. vivaxhighlights a promising role for FQ as a lead antimalarial against CQ-resistantPlasmodiumand a useful partner drug for artemisinin-based combination therapy.

scholarly journals ContrastingEx VivoEfficacies of “Reversed Chloroquine” Compounds in Chloroquine-Resistant Plasmodium falciparum and P. vivax Isolates

2015 ◽  
Vol 59 (9) ◽  
pp. 5721-5726 ◽  
Author(s):  
Grennady Wirjanata ◽  
Boni F. Sebayang ◽  
Ferryanto Chalfein ◽  
Prayoga ◽  
Irene Handayuni ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Ex Vivo ◽  
Rank Correlation ◽  
Multidrug Resistant ◽  
Content Type ◽  
Reversal Agents ◽  
Field Isolates ◽  
Spearman’S Rank Correlation ◽  
Spearman’S Rank Correlation Coefficient ◽  
Potential Use

ABSTRACTChloroquine (CQ) has been the mainstay of malaria treatment for more than 60 years. However, the emergence and spread of CQ resistance now restrict its use to only a few areas where malaria is endemic. The aim of the present study was to investigate whether a novel combination of a CQ-like moiety and an imipramine-like pharmacophore can reverse CQ resistanceex vivo. Between March to October 2011 and January to September 2013, two “reversed chloroquine” (RCQ) compounds (PL69 and PL106) were tested against multidrug-resistant field isolates ofPlasmodium falciparum(n= 41) andPlasmodium vivax(n= 45) in Papua, Indonesia, using a modifiedex vivoschizont maturation assay. The RCQ compounds showed high efficacy against both CQ-resistantP. falciparumandP. vivaxfield isolates. ForP. falciparum, the median 50% inhibitory concentrations (IC50s) were 23.2 nM for PL69 and 26.6 nM for PL106, compared to 79.4 nM for unmodified CQ (P< 0.001 andP= 0.036, respectively). The corresponding values forP. vivaxwere 19.0, 60.0, and 60.9 nM (P< 0.001 andP= 0.018, respectively). There was a significant correlation between IC50s of CQ and PL69 (Spearman's rank correlation coefficient [rs] = 0.727,P< 0.001) and PL106 (rs= 0.830,P< 0.001) inP. vivaxbut not inP. falciparum. Both RCQs were equally active against the ring and trophozoite stages ofP. falciparum, but inP. vivax, PL69 and PL106 showed less potent activity against trophozoite stages (median IC50s, 130.2 and 172.5 nM) compared to ring stages (median IC50s, 17.6 and 91.3 nM). RCQ compounds have enhancedex vivoactivity against CQ-resistant clinical isolates ofP. falciparumandP. vivax, suggesting the potential use of reversal agents in antimalarial drug development. Interspecies differences in RCQ compound activity may indicate differences in CQ pharmacokinetics between the twoPlasmodiumspecies.

scholarly journals Ex VivoActivity of Endoperoxide Antimalarials, Including Artemisone and Arterolane, against Multidrug-Resistant Plasmodium falciparum Isolates from Cambodia

2014 ◽  
Vol 58 (10) ◽  
pp. 5831-5840 ◽  
Author(s):  
Charlotte A. Lanteri ◽  
Suwanna Chaorattanakawee ◽  
Chanthap Lon ◽  
David L. Saunders ◽  
Wiriya Rutvisuttinunt ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Ex Vivo ◽  
Geometric Mean ◽  
Artemisinin Resistance ◽  
Multidrug Resistant ◽  
Chloroquine Resistance ◽  
Enzyme Linked Immunosorbent Assay ◽  
Multidrug Resistance Gene ◽  
Content Type ◽  
Clinical Resistance

ABSTRACTNovel synthetic endoperoxides are being evaluated as new components of artemisinin combination therapies (ACTs) to treat artemisinin-resistantPlasmodium falciparummalaria. We conducted blindedex vivoactivity testing of fully synthetic (OZ78 and OZ277) and semisynthetic (artemisone, artemiside, artesunate, and dihydroartemisinin) endoperoxides in the histidine-rich protein 2 enzyme-linked immunosorbent assay against 200P. falciparumisolates from areas of artemisinin-resistant malaria in western and northern Cambodia in 2009 and 2010. The order of potency and geometric mean (GM) 50% inhibitory concentrations (IC50s) were as follows: artemisone (2.40 nM) > artesunate (8.49 nM) > dihydroartemisinin (11.26 nM) > artemiside (15.28 nM) > OZ277 (31.25 nM) > OZ78 (755.27 nM).Ex vivoactivities of test endoperoxides positively correlated with dihydroartemisinin and artesunate. The isolates were over 2-fold less susceptible to dihydroartemisinin than the artemisinin-sensitiveP. falciparumW2 clone and showed sensitivity comparable to those with test endoperoxides and artesunate, with isolate/W2 IC50susceptibility ratios of <2.0. All isolates hadP. falciparumchloroquine resistance transporter mutations, with negative correlations in sensitivity to endoperoxides and chloroquine. The activities of endoperoxides (artesunate, dihydroartemisinin, OZ277, and artemisone) significantly correlated with that of the ACT partner drug, mefloquine. Isolates had mutations associated with clinical resistance to mefloquine, with 35% prevalence ofP. falciparummultidrug resistance gene 1 (pfmdr1) amplification and 84.5% occurrence of thepfmdr1Y184F mutation. GM IC50s for mefloquine, lumefantrine, and endoperoxides (artesunate, dihydroartemisinin, OZ277, OZ78, and artemisone) correlated withpfmdr1copy number. Given that current ACTs are failing potentially from reduced sensitivity to artemisinins and partner drugs, newly identified mutations associated with artemisinin resistance reported in the literature andpfmdr1mutations should be examined for their combined contributions to emerging ACT resistance.

scholarly journals Plasmodium falciparum Polymorphisms Associated withEx VivoDrug Susceptibility and Clinical Effectiveness of Artemisinin-Based Combination Therapies in Benin

2013 ◽  
Vol 58 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Sabina Dahlström ◽  
Agnès Aubouy ◽  
Oumou Maïga-Ascofaré ◽  
Jean-François Faucher ◽  
Abel Wakpo ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Ex Vivo ◽  
Clinical Effectiveness ◽  
Drug Susceptibility ◽  
Fixed Dose ◽  
Enzyme Linked Immunosorbent Assay ◽  
Recurrent Infections ◽  
Combination Therapies ◽  
Content Type ◽  
Selection Of

ABSTRACTArtemisinin-based combination therapies (ACTs) are the main option to treat malaria, and their efficacy and susceptibility must be closely monitored to avoid resistance. We assessed the association ofPlasmodium falciparumpolymorphisms andex vivodrug susceptibility with clinical effectiveness. Patients enrolled in an effectiveness trial comparing artemether-lumefantrine (n= 96), fixed-dose artesunate-amodiaquine (n= 96), and sulfadoxine-pyrimethamine (n= 48) for the treatment of uncomplicated malaria 2007 in Benin were assessed.pfcrt,pfmdr1,pfmrp1,pfdhfr, andpfdhpspolymorphisms were analyzed pretreatment and in recurrent infections. Drug susceptibility was determined in fresh baseline isolates byPlasmodiumlactate dehydrogenase enzyme-linked immunosorbent assay (ELISA). A majority had 50% inhibitory concentration (IC50) estimates (the concentration required for 50% growth inhibition) lower than those of the 3D7 reference clone for desethylamodiaquine, lumefantrine, mefloquine, and quinine and was considered to be susceptible, while dihydroartemisinin and pyrimethamine IC50s were higher. No association was found between susceptibility to the ACT compounds and treatment outcome. Selection was observed for thepfmdr1N86 allele in artemether-lumefantrine recrudescences (recurring infections) (4/7 [57.1%] versus 36/195 [18.5%]), and of the opposite allele, 86Y, in artesunate-amodiaquine reinfections (new infections) (20/22 [90.9%] versus 137/195 [70.3%]) compared to baseline infections. The importance ofpfmdr1N86 in lumefantrine tolerance was emphasized by its association with elevated lumefantrine IC50s. Genetic linkage between N86 and Y184 was observed, which together with the low frequency of 1246Y may explain regional differences in selection ofpfmdr1loci. Selection of opposite alleles in artemether-lumefantrine and artesunate-amodiaquine recurrent infections supports the strategy of multiple first-line treatment. Surveillance based on clinical,ex vivo, molecular, and pharmacological data is warranted.

scholarly journals Antimalarial Benzoxaboroles Target Plasmodium falciparum Leucyl-tRNA Synthetase

2016 ◽  
Vol 60 (8) ◽  
pp. 4886-4895 ◽  
Author(s):  
Ebere Sonoiki ◽  
Andres Palencia ◽  
Denghui Guo ◽  
Vida Ahyong ◽  
Chen Dong ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Multidrug Resistant ◽  
Trna Synthetase ◽  
Mechanisms Of Action ◽  
Unnatural Amino Acid ◽  
Leucine Incorporation ◽  
Wild Type ◽  
Content Type ◽  
Editing Domain

ABSTRACTThere is a need for new antimalarials, ideally with novel mechanisms of action. Benzoxaboroles have been shown to be active against bacteria, fungi, and trypanosomes. Therefore, we investigated the antimalarial activity and mechanism of action of 3-aminomethyl benzoxaboroles againstPlasmodium falciparum. Two 3-aminomethyl compounds, AN6426 and AN8432, demonstrated good potency against cultured multidrug-resistant (W2 strain)P. falciparum(50% inhibitory concentration [IC50] of 310 nM and 490 nM, respectively) and efficacy against murinePlasmodium bergheiinfection when administered orally once daily for 4 days (90% effective dose [ED90], 7.4 and 16.2 mg/kg of body weight, respectively). To characterize mechanisms of action, we selected parasites with decreased drug sensitivity by culturing with stepwise increases in concentration of AN6426. Resistant clones were characterized by whole-genome sequencing. Three generations of resistant parasites had polymorphisms in the predicted editing domain of the gene encoding aP. falciparumleucyl-tRNA synthetase (LeuRS; PF3D7_0622800) and in another gene (PF3D7_1218100), which encodes a protein of unknown function. Solution of the structure of theP. falciparumLeuRS editing domain suggested key roles for mutated residues in LeuRS editing. Short incubations with AN6426 and AN8432, unlike artemisinin, caused dose-dependent inhibition of [14C]leucine incorporation by cultured wild-type, but not resistant, parasites. The growth of resistant, but not wild-type, parasites was impaired in the presence of the unnatural amino acid norvaline, consistent with a loss of LeuRS editing activity in resistant parasites. In summary, the benzoxaboroles AN6426 and AN8432 offer effective antimalarial activity and act, at least in part, against a novel target, the editing domain ofP. falciparumLeuRS.

scholarly journals In vitro evaluation of erythromycin in chloroquine resistant brazilian P. falciparum freshly isolates: modulating effect and antimalarial activity evidence

1999 ◽  
Vol 41 (4) ◽  
pp. 249-253 ◽  
Author(s):  
Carla M. S. MENEZES ◽  
Karin KIRCHGATTER ◽  
Sílvia M. F. DI SANTI ◽  
Carine SAVALLI ◽  
Fabíola G. MONTEIRO ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimicrobial Therapy ◽  
Antimalarial Activity ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Chloroquine Resistance ◽  
Reversal Agent ◽  
Resistance Modulation ◽  
Erythromycin A

Erythromycin, a reversal agent in multidrug-resistant cancer, was assayed in chloroquine resistance modulation. The in vitro microtechnique for drug susceptibility was employed using two freshly isolates of Plasmodium falciparum from North of Brazil. The antimalarial effect of the drug was confirmed, with an IC50 estimates near the usual antimicrobial therapy concentration, and a significant statistical modulating action was observed for one isolate.

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