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Analysis of dihydrofolate reductase ...

Hastings, Michele Dawn.

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Analysis of dihydrofolate reductase variations in relation to antifolate resistance in Plasmodium vivax.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Analysis of dihydrofolate reductase variations in relation to antifolate resistance in Plasmodium vivax./
Author:	Hastings, Michele Dawn.
Description:	127 p.
Notes:	Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 4963.
Contained By:	Dissertation Abstracts International65-10B.
Subject:	Biology, Genetics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3151610
ISBN:	0496120298

Analysis of dihydrofolate reductase variations in relation to antifolate resistance in Plasmodium vivax.
Hastings, Michele Dawn.

Analysis of dihydrofolate reductase variations in relation to antifolate resistance in Plasmodium vivax. - 127 p.

Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 4963.

Thesis (Ph.D.)--University of Washington, 2004.

The Plasmodium vivax parasite causes relapsing malaria, a severe and debilitating febrile illness. It is the prevalent cause of human malaria outside of Subsaharan Africa, contributing an estimated 80 million cases annually, and exerts a significant toll on the health and economic prosperity of countries in tropical and subtropical regions. Infection is typically treated with chloroquine and primaquine, but rising resistance to these drugs has been observed in recent years. Pyrimethamine, a drug that acts as a competitive inhibitor of the dihydrofolate reductase (DHFR) enzyme of Apicomplexan parasites, was tested against P. vivax in the 1950s, but was not judged to be sufficiently effective. My research has addressed two questions. Why were initial trials of pyrimethamine treatment unsuccessful, and are there novel antifolates that might be effective against P. vivax? When I began, very little was known about which dhfr alleles confer pyrimethamine resistance or their prevalence in the P. vivax population. I conducted an informal survey of alleles in Indonesia and Papua New Guinea, where drug resistance in malaria is particularly problematic, and identified several novel and highly resistant dhfr alleles. P. vivax cannot be maintained in the lab, so I have also introduced alleles of P. vivax dhfr into lines of yeast that lack endogenous DHFR expression to create an in vitro assay for drug resistance. I have correlated the results of the in vitro yeast assay with clinical outcomes for patients treated with the fixed combination of pyrimethamine/sulfadoxine, the standard of treatment for presumptive malaria in many endemic countries. Using the in vitro assay, my research also revealed substantial cross-resistance between pyrimethamine and the active metabolite of chlorproguanil, the antifolate component of the recently deployed combination antimalarial drug Lapdap. However, many of the most pyrimethamine-resistant P. vivax dhfr alleles are sensitive or even hypersensitive to the novel antifolate WR99210. As a result of my work, which spans the spectrum from basic lab-based experiments to clinical and field studies, a close analog of WR99210 is being developed for treatment of highly pyrimethamine-resistant P. vivax parasites that are common in regions of Thailand and Indonesia.

ISBN: 0496120298Subjects--Topical Terms:

1017730
Biology, Genetics.

Analysis of dihydrofolate reductase variations in relation to antifolate resistance in Plasmodium vivax.
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100 1 $a Hastings, Michele Dawn. $3 1931762
245 1 0 $a Analysis of dihydrofolate reductase variations in relation to antifolate resistance in Plasmodium vivax.
300 $a 127 p.
500 $a Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 4963.
500 $a Chair: Carol Hopkins Sibley.
502 $a Thesis (Ph.D.)--University of Washington, 2004.
520 $a The Plasmodium vivax parasite causes relapsing malaria, a severe and debilitating febrile illness. It is the prevalent cause of human malaria outside of Subsaharan Africa, contributing an estimated 80 million cases annually, and exerts a significant toll on the health and economic prosperity of countries in tropical and subtropical regions. Infection is typically treated with chloroquine and primaquine, but rising resistance to these drugs has been observed in recent years. Pyrimethamine, a drug that acts as a competitive inhibitor of the dihydrofolate reductase (DHFR) enzyme of Apicomplexan parasites, was tested against P. vivax in the 1950s, but was not judged to be sufficiently effective. My research has addressed two questions. Why were initial trials of pyrimethamine treatment unsuccessful, and are there novel antifolates that might be effective against P. vivax? When I began, very little was known about which dhfr alleles confer pyrimethamine resistance or their prevalence in the P. vivax population. I conducted an informal survey of alleles in Indonesia and Papua New Guinea, where drug resistance in malaria is particularly problematic, and identified several novel and highly resistant dhfr alleles. P. vivax cannot be maintained in the lab, so I have also introduced alleles of P. vivax dhfr into lines of yeast that lack endogenous DHFR expression to create an in vitro assay for drug resistance. I have correlated the results of the in vitro yeast assay with clinical outcomes for patients treated with the fixed combination of pyrimethamine/sulfadoxine, the standard of treatment for presumptive malaria in many endemic countries. Using the in vitro assay, my research also revealed substantial cross-resistance between pyrimethamine and the active metabolite of chlorproguanil, the antifolate component of the recently deployed combination antimalarial drug Lapdap. However, many of the most pyrimethamine-resistant P. vivax dhfr alleles are sensitive or even hypersensitive to the novel antifolate WR99210. As a result of my work, which spans the spectrum from basic lab-based experiments to clinical and field studies, a close analog of WR99210 is being developed for treatment of highly pyrimethamine-resistant P. vivax parasites that are common in regions of Thailand and Indonesia.
590 $a School code: 0250.
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650 4 $a Health Sciences, Pathology. $3 1017854
650 4 $a Health Sciences, Pharmacology. $3 1017717
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710 2 0 $a University of Washington. $3 545923
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791 $a Ph.D.
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