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Inhibitory effect of artemisinin com...

Mishina, Yuliya V.

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Inhibitory effect of artemisinin compounds on Leishmania and Trypanosoma parasites.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Inhibitory effect of artemisinin compounds on Leishmania and Trypanosoma parasites./
Author:	Mishina, Yuliya V.
Description:	101 p.
Notes:	Adviser: John C. Meade.
Contained By:	Dissertation Abstracts International68-02B.
Subject:	Biology, Microbiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3252940

Inhibitory effect of artemisinin compounds on Leishmania and Trypanosoma parasites.
Mishina, Yuliya V.

Inhibitory effect of artemisinin compounds on Leishmania and Trypanosoma parasites. - 101 p.

Adviser: John C. Meade.

Thesis (Ph.D.)--The University of Mississippi Medical Center, 2007.

Leishmania donovani, L. major, and L. braziliensis (visceral, cutaneous, and mucocutaneous leishmaniasis), and the trypanosomatid parasites Trypanosoma cruzi (American Chagas disease) and T. brucei (African Sleeping sickness) are significant causes of morbidity and mortality worldwide. Current drug treatments for these pathogens have toxic side effects and are only partially effective. There is an urgent need for improved chemoprophylactic regimens for these human pathogens. Artemisinin and its derivatives are safe, highly effective antimalarial drugs that target the Plasmodium endoplasmic reticulum calcium pump (SERCA). Evidence from the studies described here indicates that artemisinin and its derivatives inhibit growth of cultured Leishmania and Trypanosoma parasites, including a recent L. major clinical isolate, by 50% (IC50) at low micromolar concentrations. Artemisinins also inhibit L. donovani promastigotes at pH 5.5 and amastigotes in human U-937 monocytes at similar concentrations. Drug exposure need not be continuous to inhibit growth as 8 hr daily drug exposure also achieves IC50 at low micromolar concentrations. Although current anti-leishmanial drugs, amphotericin B and pentamidine, were more potent against parasites than artemisinins, they were far more toxic to U-937 cells and artemisinins offer a wider therapeutic window. Resistance of L. donovani to artemisinins was quite difficult to obtain with only a 7 fold increase in IC50 achieved after 8 months, indicating that development of parasite drug resistance during treatment is not likely. The mechanism of this resistance was not identified but did not involve SERCA gene amplification or mutation. The L. donovani SERCA pump was identified as the cellular target of artemisinin activity based on antagonism between artemisinin and thapsigargin, another SERCA inhibitor, as shown in isobologram analysis, inhibition of LDSERCA activity in isolated parasite membranes by artemisinin, and by concentration dependent blockage of fluorescent thapsigargin (BODIPY-thapsigargin) labeling of L. donovani promastigotes by unlabeled artemisinin. Artemisinin compounds possess anti-parasite activity sufficiently robust to merit consideration as a therapeutic option, providing a unique opportunity to exploit a novel class of drugs with an excellent safety profile. Identification of SERCA pump inhibition as the mode of artemisinin activity will also facilitate future development of artemisinins by enabling molecular modeling of artemisinin-SERCA interactions.Subjects--Topical Terms:

1017734
Biology, Microbiology.

Inhibitory effect of artemisinin compounds on Leishmania and Trypanosoma parasites.
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035 $a (UMI)AAI3252940
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100 1 $a Mishina, Yuliya V. $3 1267689
245 1 0 $a Inhibitory effect of artemisinin compounds on Leishmania and Trypanosoma parasites.
300 $a 101 p.
500 $a Adviser: John C. Meade.
500 $a Source: Dissertation Abstracts International, Volume: 68-02, Section: B, page: 0759.
502 $a Thesis (Ph.D.)--The University of Mississippi Medical Center, 2007.
520 $a Leishmania donovani, L. major, and L. braziliensis (visceral, cutaneous, and mucocutaneous leishmaniasis), and the trypanosomatid parasites Trypanosoma cruzi (American Chagas disease) and T. brucei (African Sleeping sickness) are significant causes of morbidity and mortality worldwide. Current drug treatments for these pathogens have toxic side effects and are only partially effective. There is an urgent need for improved chemoprophylactic regimens for these human pathogens. Artemisinin and its derivatives are safe, highly effective antimalarial drugs that target the Plasmodium endoplasmic reticulum calcium pump (SERCA). Evidence from the studies described here indicates that artemisinin and its derivatives inhibit growth of cultured Leishmania and Trypanosoma parasites, including a recent L. major clinical isolate, by 50% (IC50) at low micromolar concentrations. Artemisinins also inhibit L. donovani promastigotes at pH 5.5 and amastigotes in human U-937 monocytes at similar concentrations. Drug exposure need not be continuous to inhibit growth as 8 hr daily drug exposure also achieves IC50 at low micromolar concentrations. Although current anti-leishmanial drugs, amphotericin B and pentamidine, were more potent against parasites than artemisinins, they were far more toxic to U-937 cells and artemisinins offer a wider therapeutic window. Resistance of L. donovani to artemisinins was quite difficult to obtain with only a 7 fold increase in IC50 achieved after 8 months, indicating that development of parasite drug resistance during treatment is not likely. The mechanism of this resistance was not identified but did not involve SERCA gene amplification or mutation. The L. donovani SERCA pump was identified as the cellular target of artemisinin activity based on antagonism between artemisinin and thapsigargin, another SERCA inhibitor, as shown in isobologram analysis, inhibition of LDSERCA activity in isolated parasite membranes by artemisinin, and by concentration dependent blockage of fluorescent thapsigargin (BODIPY-thapsigargin) labeling of L. donovani promastigotes by unlabeled artemisinin. Artemisinin compounds possess anti-parasite activity sufficiently robust to merit consideration as a therapeutic option, providing a unique opportunity to exploit a novel class of drugs with an excellent safety profile. Identification of SERCA pump inhibition as the mode of artemisinin activity will also facilitate future development of artemisinins by enabling molecular modeling of artemisinin-SERCA interactions.
590 $a School code: 0805.
650 4 $a Biology, Microbiology. $3 1017734
650 4 $a Biology, Parasitology. $3 1028974
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710 2 $a The University of Mississippi Medical Center. $3 1017852
773 0 $t Dissertation Abstracts International $g 68-02B.
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790 1 0 $a Meade, John C., $e advisor
791 $a Ph.D.
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856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3252940