Artemether-Lumefantrine Selects For Malaria Parasites With Decreased Lumefantrine Sensitivity Although Parasites Remain Sensitive To This Regimen In Tororo, Uganda, P. Tumwebaze, J. Bloome, O. Byaruhanga, C. Nakazibwe, A. Walakira, J. Okiring, S. L. Nsobya, Roland A. Cooper, P. J. Rosenthal
Nov 2012
Artemether-Lumefantrine Selects For Malaria Parasites With Decreased Lumefantrine Sensitivity Although Parasites Remain Sensitive To This Regimen In Tororo, Uganda, P. Tumwebaze, J. Bloome, O. Byaruhanga, C. Nakazibwe, A. Walakira, J. Okiring, S. L. Nsobya, Roland A. Cooper, P. J. Rosenthal
Roland A. Cooper
Artemisinin-based combination therapies (ACTs) may select for malaria parasites with decreased drug sensitivity. We studied the sensitivity of parasites from children enrolled in treatment and prevention trials in Tororo, Uganda from June, 2010 to February, 2012. When Plasmodium falciparum malaria was diagnosed, blood was obtained, parasites (286 isolates) were cultured with serial dilutions of chloroquine (CQ), monodesethylamodiaquine (AQ), quinine (QN), dihydroartemisinin (DHA), lumefantrine (LM), or piperaquine (PQ) for 72 h, and ex vivo sensitivities were assessed by HRP-2-based ELISA. Sensitivities (nM) to CQ (median IC50 486.2; IQR 206.5-748.8), AQ (83.3; 58.4-132.4), PQ (20.3; 7.6-47.5) and QN (126.4; 74.9-196.3) varied widely; …
Molecular Action Of 1,2,4-Trioxolanes In Plasmodium Falciparum, R. A. Cooper, C. L. Hartwig, E. Lauterwasser, S. Mahajan, M. Hoke, A. Renslo
Dec 2011
Molecular Action Of 1,2,4-Trioxolanes In Plasmodium Falciparum, R. A. Cooper, C. L. Hartwig, E. Lauterwasser, S. Mahajan, M. Hoke, A. Renslo
Roland A. Cooper
No abstract provided.
Ex Vivo Drug Sensitivity Of Malaria Parasites Under Selective Pressure In Tororo, Uganda, P. K. Tumebaze, O. Byaruhanga, J. Okiring, S. L. Nsobya, R. A. Cooper, P. J. Rosenthal
Nov 2011
Ex Vivo Drug Sensitivity Of Malaria Parasites Under Selective Pressure In Tororo, Uganda, P. K. Tumebaze, O. Byaruhanga, J. Okiring, S. L. Nsobya, R. A. Cooper, P. J. Rosenthal
Roland A. Cooper
Artemisinin-based combination therapies (ACTs) are standard treatments for uncomplicated malaria in Africa. ACTs provide highly effective treatment, and regular use may offer protection against malaria in high risk populations. However, increased use of ACTs may select for parasites with decreased sensitivity. We studied the ex vivo sensitivity of malaria parasites collected from children enrolled in treatment and prevention trials in Tororo, Uganda from June, 2010 to August, 2011. When P. falciparum malaria was diagnosed, blood was obtained, parasites were cultured with serial dilutions of chloroquine (CQ), monodesethylamodiaquine (AQ), quinine (QN), dihydroartemisinin (DHA), lumefantrine (LM), and piperaquine (PQ) for 72 hours, …
Discovery Of Dual Function Acridones As A New Antimalarial Chemotype, Jane X. Kelly, Martin J. Smilkstein, Reto Brun, Sergio Wittlin, Roland A. Cooper, Kristin D. Lane, Aaron Janowsky, Robert A. Johnson, Rozalia A. Dodean, Rolf Winter, David J. Hinrichs, Michael K. Riscoe
May 2009
Discovery Of Dual Function Acridones As A New Antimalarial Chemotype, Jane X. Kelly, Martin J. Smilkstein, Reto Brun, Sergio Wittlin, Roland A. Cooper, Kristin D. Lane, Aaron Janowsky, Robert A. Johnson, Rozalia A. Dodean, Rolf Winter, David J. Hinrichs, Michael K. Riscoe
Roland A. Cooper
Preventing and delaying the emergence of drug resistance is an essential goal of antimalarial drug development. Monotherapy and highly mutable drug targets have each facilitated resistance, and both are undesirable in effective long-term strategies against multi-drug-resistant malaria. Haem remains an immutable and vulnerable target, because it is not parasite-encoded and its detoxification during haemoglobin degradation, critical to parasite survival, can be subverted by drug-haem interaction as in the case of quinolines and many other drugs. Here we describe a new antimalarial chemotype that combines the haem-targeting character of acridones, together with a chemosensitizing component that counteracts resistance to quinoline antimalarial …
Stage Independent Chloroquine Resistance And Chloroquine Toxicity Revealed Via Spinning Disk Confocal Microscopy, Bojana Gligorijevic, Kyle Purdy, David A. Elliott, Roland A. Cooper, Paul D. Roepe
Apr 2008
Stage Independent Chloroquine Resistance And Chloroquine Toxicity Revealed Via Spinning Disk Confocal Microscopy, Bojana Gligorijevic, Kyle Purdy, David A. Elliott, Roland A. Cooper, Paul D. Roepe
Roland A. Cooper
We previously customized a Nipkow spinning disk confocal microscope (SDCM) to acquire 4D data for live, intraerythrocytic malarial parasites [Gligorijevic B, McAllister R, Urbach JS, Roepe, PD. Spinning disk confocal microscopy of live, intraerythrocytic malarial parasites. 1. Quantification of hemozoin development for drug sensitive versus resistant malaria. Biochemistry 2006;45:12400-10]. We reported that chloroquine (CQ) treatment did not appear to affect progress through the cell cycle, and suggested that toxicity may be manifested post-schizogony. We now use SDCM, synchronized cell culture and continuous vs. bolus drug dosing to investigate stage specific CQ effects in detail. We develop a novel, extremely rapid …
Pfcg2, A Plasmodium Falciparum Protein Peripherally Associated With The Parasitophorous Vacuolar Membrane, Is Expressed In The Period Of Maximum Hemoglobin Uptake And Digestion By Trophozoites, Roland A. Cooper, Janni Papakrivos, Kristen D. Lane, Hisashi Fujioka, Klaus Lingelbach, Thomas E. Wellems
Nov 2005
Pfcg2, A Plasmodium Falciparum Protein Peripherally Associated With The Parasitophorous Vacuolar Membrane, Is Expressed In The Period Of Maximum Hemoglobin Uptake And Digestion By Trophozoites, Roland A. Cooper, Janni Papakrivos, Kristen D. Lane, Hisashi Fujioka, Klaus Lingelbach, Thomas E. Wellems
Roland A. Cooper
A Plasmodium falciparum gene closely linked to the chloroquine resistance locus encodes PfCG2, a predicted 320-330kDa protein. In the parasitized erythrocyte, PfCG2 expression rises sharply in the trophozoite stage and is detected in electron-dense patches along the parasitophorous vacuolar membrane (PVM), in the cytoplasm and in the digestive vacuole (DV). Results of extraction and partitioning experiments show that PfCG2 is a peripheral membrane protein. Exposure of trophozoite-infected erythrocytes to trypsin-containing buffer after streptolysin O permeabilization indicates that PfCG2 is exposed to the erythrocyte cytosol at the outer face of the PVM. PfCG2 is highly susceptible to hydrolysis by aspartic and …
Pfcrt Is More Than The Plasmodium Falciparum Chloroquine Resistance Gene: A Functional And Evolutionary Perspective, Roland A. Cooper, Carmony L. Hartwig, Michael T. Ferdig
May 2005
Pfcrt Is More Than The Plasmodium Falciparum Chloroquine Resistance Gene: A Functional And Evolutionary Perspective, Roland A. Cooper, Carmony L. Hartwig, Michael T. Ferdig
Roland A. Cooper
Genetic, physiological and pharmacological studies are gradually revealing the molecular basis of chloroquine resistance (CQR) in the malaria parasite, Plasmodium falciparum. Recent highlights include the discovery of a key gene associated with resistance, pfcrt (Plasmodium falciparum chloroquine resistance transporter; PfCRT), encoding a novel transporter, and the characterization of global selective sweeps of haplotypes containing a K76T amino acid change within this protein. Little is known about the cellular mechanism by which resistant parasites escape the effects of chloroquine (CQ), one of the most promising drugs ever deployed, due in part to an unresolved mechanism of action. The worldwide spread of …
Proteomic Approaches To Studying Drug Targets And Resistance In Plasmodium, R. A. Cooper, D. J. Carucci
Feb 2004
Proteomic Approaches To Studying Drug Targets And Resistance In Plasmodium, R. A. Cooper, D. J. Carucci
Roland A. Cooper
Ever increasing drug resistance by Plasmodium falciparum, the most virulent of human malaria parasites, is creating new challenges in malaria chemotherapy. The entire genome sequences of P. falciparum and the rodent malaria parasite, P. yoelii yoelii are now available. Extensive genome sequence data from other Plasmodium species including another important human malaria parasite, P. vivax are also available. Powerful research techniques coupled to genomic resources are needed to help identify new drug and vaccine targets against malaria. Applied to Plasmodium, proteomics combines high-resolution protein or peptide separation with mass spectrometry and computer software to rapidly identify large numbers of proteins …
Plasmepsin 4, The Food Vacuole Aspartic Proteinase Found In All Plasmodium Spp. Infecting Man, John B. Dame, Charles A. Yowell, Levi Omara-Opyene, Jane M. Carlton, Roland A. Cooper, Tang Li
Jul 2003
Plasmepsin 4, The Food Vacuole Aspartic Proteinase Found In All Plasmodium Spp. Infecting Man, John B. Dame, Charles A. Yowell, Levi Omara-Opyene, Jane M. Carlton, Roland A. Cooper, Tang Li
Roland A. Cooper
Plasmepsins are aspartic proteinases of the malaria parasite, and seven groups of plasmepsins have been identified by comparing genomic sequence data available for the genes encoding these enzymes from Plasmodium falciparum, Plasmodium vivax, Plasmodium knowlesi, Plasmodium berghei, and Plasmodium yoelii. The food vacuole plasmepsins typified by plasmepsin 4 from P. falciparum (PfPM4) constitute one of these groups. Genes encoding the ortholog of PfPM4 have been cloned from Plasmodium ovale, Plasmodium malariae, and P. vivax. In addition, P. falciparum contains three paralagous food vacuole plasmepsins or plasmepsin-like enzymes that appear to have arisen by gene duplication, plasmepsins 1 (PfPM1), 2 (PfPM2) …
Genetic Diversity And Chloroquine Selective Sweeps In Plasmodium Falciparum, John C. Wootton, Xiaorong Feng, Michael T. Ferdig, Roland A. Cooper, Jianbing Mu, Dror I. Baruch, Alan J. Magill, Xin-Zhuan Su
Jul 2002
Genetic Diversity And Chloroquine Selective Sweeps In Plasmodium Falciparum, John C. Wootton, Xiaorong Feng, Michael T. Ferdig, Roland A. Cooper, Jianbing Mu, Dror I. Baruch, Alan J. Magill, Xin-Zhuan Su
Roland A. Cooper
Widespread use of antimalarial agents can profoundly influence the evolution of the human malaria parasite Plasmodium falciparum. Recent selective sweeps for drug-resistant genotypes may have restricted the genetic diversity of this parasite, resembling effects attributed in current debates to a historic population bottleneck. Chloroquine-resistant (CQR) parasites were initially reported about 45 years ago from two foci in southeast Asia and South America, but the number of CQR founder mutations and the impact of chlorquine on parasite genomes worldwide have been difficult to evaluate. Using 342 highly polymorphic microsatellite markers from a genetic map, here we show that the level of …
P. Falciparum Cg2, Linked To Chloroquine Resistance, Does Not Resemble Na+/H+ Exchangers, Thomas E. Wellems, John C. Wootton, Hisashi Fujioka, Xin-Zhuan Su, Roland Cooper, Dror Baruch, David A. Frock
Aug 1998
P. Falciparum Cg2, Linked To Chloroquine Resistance, Does Not Resemble Na+/H+ Exchangers, Thomas E. Wellems, John C. Wootton, Hisashi Fujioka, Xin-Zhuan Su, Roland Cooper, Dror Baruch, David A. Frock
Roland A. Cooper
Understanding the molecular basis for chloroquine resistance in Plasmodium falciparum will provide important support for the development of new therapies and prophylactic measures against malaria. Complementary genetic and biochemical investigations should discriminate among current theories and pinpoint the functional determinants of resistance. With this in mind Sanchez et al. 1998 have proposed that the P. falciparum cg2 gene, linked by Su et al. 1997 to chloroquine resistance, may encode a sodium/hydrogen exchanger (NHE) responsible for drug transport. Here, we present evidence against this proposal. Detailed reanalysis of the CG2 sequence fails to support the claims for significant similarity to functional …
Preparative Separation Of Pyrrolizidine Alkaloids By High-Speed Counter-Current Chromatography, Roland A. Cooper, Rion J. Bowers, Carla J. Beckham, Ryan J. Huxtable
Apr 1996
Preparative Separation Of Pyrrolizidine Alkaloids By High-Speed Counter-Current Chromatography, Roland A. Cooper, Rion J. Bowers, Carla J. Beckham, Ryan J. Huxtable
Roland A. Cooper
We have applied a high-speed counter-current chromatography (CCC) technique to the separation and purification of pyrrolizidine alkaloids from Amsinckia tessellata, Symphytum spp., Trichodesma incanum (Boraginaceae), and Senecio douglasii var. longilobus (Asteraceae). Alkaloidal fractions were separated in a solvent system composed of a chloroform mobile phase and 0.2 M potassium phosphate buffer, of an optimum pH, as the stationary phase. Up to 800 mg of sample could be successfully separated in a single run, with excellent resolution of alkaloids. Lycopsamine and several of its acetylated derivatives were resolved from alkaloidal fractions of Amsinckia and Symphytum. However, diastereomeric pairs such as 7-acetyl-lycopsamine …
The Comparative Metabolism Of The Four Pyrrolizidine Alkaloids, Seneciphylline, Retrorsine, Monocrotaline, And Trichodesmine In The Isolated, Perfused Rat Liver., C. C. Yan, R. A. Cooper, R. J. Huxtable
Jul 1995
The Comparative Metabolism Of The Four Pyrrolizidine Alkaloids, Seneciphylline, Retrorsine, Monocrotaline, And Trichodesmine In The Isolated, Perfused Rat Liver., C. C. Yan, R. A. Cooper, R. J. Huxtable
Roland A. Cooper
Despite their similarity in structure, pyrrolizidine alkaloids (PAs) vary in their LD50s and in the organs in which toxicity is expressed. We have examined whether there are differences in the metabolism of certain PAs that are associated with these quantitative and qualitative differences in toxicity. Isolated rat livers were perfused with one of four PAs (seneciphylline, retrorsine, monocrotaline, and trichodesmine) at 0.5 mM for 1 hr, and the pyrrolic metabolites determined that were released into perfusate and bile or bound in the liver. The proportion of the PA removed by the liver varied from 93% for retrorsine to 55% for …
