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Cover for Investigating the Cytostatic and Cytocidal Mechanisms of Quinoline Drug Resistance in Plasmodium falciparum
dc.contributor.advisorRoepe, Paul Den
dc.creatoren
dc.date.accessioned2013-06-07T19:27:22Zen
dc.date.available2013-06-07T19:27:22Zen
dc.date.created2013en
dc.date.issueden
dc.date.submitted01/01/2013en
dc.identifier.otherAPT-BAG: georgetown.edu.10822_558232.tar;APT-ETAG: 756edc7b2ae8a6499bf6085f607a22afen
dc.identifier.urien
dc.descriptionPh.D.en
dc.description.abstractEfficacy of, mechanisms of action of, and resistance to chemotherapeutic agents targeted against the malarial parasite Plasmodium falciparum have historically been defined by quantifying cytostatic potency or growth-inhibition. However, recent evidence has suggested that, for some drugs, this is distinct from cytocidal potency or ability to promote cell death. From a practical standpoint, the major difference lies in level and duration of drug exposure. It becomes important, then, to define both new and established aspects of drug pharmacology from the perspective of cytocidal activity.en
dc.description.abstractThe cytostatic target of quinoline-based and related drugs is generally accepted to be crystallization of ferriprotoporphyrin IX heme, a consequence of parasitic hemoglobin digestion within the digestive vacuole. It is not known, however, whether this is the predominant target for cytocidal activity.en
dc.description.abstractThe cytostatic antiplasmodial effect is exerted via drug interacting with one or more pre-crystalline forms of heme that then prevents crystallization to hemozoin. This is a complex process, as heme/drug solubility and speciation and drug-heme interactions are highly dependent on pH, ionic strength, and lipid environment. Surprisingly, the molecular details of these interactions and how they influence antimalarial activity are largely unknown for many quinoline drugs, in particular, the Cinchona alkaloid quinine.en
dc.description.abstractThis thesis further defines cytostatic vs. cytocidal antimalarial activities for quinine and its stereoisomers as well as structural analogues of quinine and chloroquine. Using these compounds, I investigate the relationship between these two antiplasmodial measurements and a drug's ability to inhibit heme crystallization. I characterize quinine- and quinine stereoisomer-heme interactions and determine the activity-relevant complexes these drugs form with heme. Finally, in collaboration with several groups, I identify novel drug leads with potent activities against resistant P. falciparum. I also develop several interdisciplinary techniques for conducting such analyses, including high-throughput drug screening, organic synthesis, and spectroscopic methods.en
dc.description.abstractCollectively, this work provides additional insight into cytostatic and cytocidal quinoline drug pharmacology and assists development of new, efficacious drugs in the fight against resistance.en
dc.formatPDFen
dc.format.extent313 leavesen
dc.languageenen
dc.publisherGeorgetown Universityen
dc.sourceGeorgetown University-Graduate School of Arts & Sciencesen
dc.sourceChemistryen
dc.subjectChloroquineen
dc.subjectfalciparumen
dc.subjectHemeen
dc.subjectHemozoinen
dc.subjectMalariaen
dc.subjectQuinineen
dc.subject.lcshChemistryen
dc.subject.lcshPharmacologyen
dc.subject.otherChemistryen
dc.subject.otherPharmacologyen
dc.titleInvestigating the Cytostatic and Cytocidal Mechanisms of Quinoline Drug Resistance in Plasmodium falciparumen
dc.typethesisen


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