Graduation Year

2015

Document Type

Thesis

Degree

M.S.P.H.

Degree Name

MS in Public Health (M.S.P.H.)

Degree Granting Department

Global Health

Major Professor

Dennis E. Kyle, Ph.D.

Committee Member

Azliyati Azizan, Ph.D.

Committee Member

Wilbur Milhous, Ph.D.

Keywords

Discontinuous Pulse Drug Exposure, Dormant Parasites, Drug Resistance, Malaria

Abstract

Combating drug resistant malaria has been historically challenging, and remains so today. Recent reports from Southeast Asia show that Plasmodium falciparum is developing resistance to even our best defenses; artemisinin-based therapies. This development threatens to become a significant challenge in controlling malaria infections worldwide, making research into developing and characterizing new antimalarial drugs increasingly important. The purpose of this study was to characterize the resistance potential of novel antimalarial compound JPC-3210 in vitro using P. falciparum clones. JPC-3210 is a new long acting drug with potential to be used in combination with fast-acting drugs like artemisinins to cure drug resistant malaria. In this study several methods were used to characterize the efficacy and resistance potential of JPC-3210. To determine the frequency of resistance generation in P. falciparum clones, parasites were kept under continuous drug pressure for thirty days, at which point drug pressure was removed and cultures were observed for signs of recrudescence. P. falciparum clones also were exposed to increasing levels of intermittent drug pressure that involved 3-4 days of drug exposure followed by a recovery period. The step-wise experiment was conducted over three months with drug pressure being increased step-wise until a maximal concentration of 700 ng/ml of JPC-3210; resistance was measured phenotypically in drug susceptibility assays at multiple time points. Additionally, the ability of JPC-3210 to induce dormant stage parasites, and its effect on dihydroartemisinin (DHA)-induced dormant stages was assessed in both a chloroquine resistant parasite (W2) and in an artemisinin resistant clone (4G). Results showed that the frequency of resistance against JPC-3210 in W2 clones was less when compared to that of atovaquone. The step-wise pulse exposure of JPC-3210 induced resistance in W2 clones, however, resistance proved unstable. Dormant stage parasites were not induced by JPC-3210, even at high concentrations in W2 or 4G clones, furthermore, the effect of JPC-3210 on dormant-induced parasites was found to be dose dependent, yet the drug did not kill DHA-induced dormant rings. JPC-3210 appears to be a good drug to use in combination with other antimalarial compounds for treatment of P. falciparum, but further research is needed. Future studies to assess the field performance of new antimalarial compounds by investigating resistance and dormancy profiles in vitro, and thereby maximizing out understanding of such drugs and their optimal implementation, are of the utmost importance.

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