| Co-Investigator(Kenkyū-buntansha) |
MORIYAMA Yoshinori Okayama University Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (10150658)
NOJIMA Masatomo Osaka University the Graduate School of Engineering, Professor, 大学院・工学研究科, 教授 (80029181)
HYES-OOK Kim Okayama University the Graduate School of Natural Sciences and Technology, Assistant Professor, 大学院・自然科学研究科, 助教授 (70314664)
SASAKI Kenji Okayama University Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (20116461)
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| Research Abstract |
Malaria remains a major health problem throughout developing parts of the world, Further spread of drug-resistant malaria against chloroquine, mefloquine, proguanile and many other available drugs, extremely limited our ability to control malaria. This terrible situation has stimulated urgent need for the development of novel antimalarial drugs, optimal use of existing drugs and development of new approach to antimalarial chemotherapy. In this study, I investigated endoperoxides as new antiplasmodial agents and analysis of mefloquine resistance mechanisms and drug interactions.
Synthesized endoperoxide 1,2,6,7-Tetraoxaspiro (7.11) nonadecane (N-89) exhibited significant antimalarial activity in vitro (IC_50 28 nM, FCR-3 strain) and in vivo (ED_50 20 mgkg^<-1>). N-89 is more effective on early and middle trophozoites stage parasites than that of late trophozoites and schizonts stage parasites. Consistance with stage-specific effect, inhibition of hemozoin formation is pronounced at matur
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e stage parasites than schizonts. Inhibition of hemoglobin digestion was found in mature stage parasites with N-89 treatment. Furthermore, antagonistic effects found when combined with protease inhibitors and explain N-89 inhibits parasite hemoglobin degradation. In a combination study with artemisinin, N-89 exhibited synergistic effect in vitro against chloroquine-resistant (K-1) and chloroquine-sensitive (FCR-3) strains. N-89 and artemisinin combination led marked decline of parasitemia and extends survival rate of mice infected with P. berghei. In vitro this combination able to complete prevention of parasites recrudescence where either drug associate with high rate of recrudesince. N-89 showed synergistic effects with artemisinin and halofantrine; additive effect with quinine; and antagonistic effect with chloroquine, mefloquine and pyrimethamine.
Sequence polymorphisms and expression level of pfmdr1 gene in highly mefloquine-resistant clone 24 were analyzed to understand underlying mefloquine resistance mechanisms in Plasmodium falciparum. The mefloquine-resistant clone/24 exerted decreased sensitivity to mefloquine, halofantrine, quinine, artemisinin, and increased sensitivity to chloroquine. There were no difference of pfmdr1 gene sequences of amino acid residues 86, 184, 1034, 1042 and 1246 among mefloquine-sensitive strain and mefloquine-resistant clone/24. In contrast, we found new mutation of T to C in pfmdr1 gene of clone/24. Furthermore, over expression of mRNA of pfmdr1 gene has been observed in resistant clone/24 than sensitive strain. It is likely that expression level and point mutation of pfmdr1 gene may be related to mefloquine resistance mechanism. Less
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