malaria treatment (references: pubmed, google, ginsburg h and golenser j publications)
DESCRIPTION
Malaria treatment (References: PubMed, Google, Ginsburg H and Golenser J publications). CHING-HAO (Artemisinin) is isolated from Artemisia annua and used in chinese medicine. Trophozoite- EM. Labile iron in P.falciparum infected erythrocytes induce fragmentation of DNA. - PowerPoint PPT PresentationTRANSCRIPT
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Malaria treatment(References: PubMed, Google, Ginsburg H
and Golenser J publications)
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CHING-HAO (Artemisinin) is isolated from Artemisia annua and used in chinese medicine
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Trophozoite- EM
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Labile iron in P.falciparum infected erythrocytes induce fragmentation of DNA
Fe2+ + H2O2 ----> Fe3+ + .OH + OH-
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Ridley RG, Nature. 2003, 424 (6951): 887-9
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Artemisinin inhibits plasmodia by two mechanisms:
1. Production of free radicals which affects different macromolecules.
2. Specific interference with PfATP6 (Ca-2+ATPase (SERCA)). This interference is also mediated by iron induced damage.Thapsigargin is an inhibitor of SERCA, has structural similarity to artemisinin, lacks peroxide bridge and interferes with the anti-plasmodial activity of artemisinin.Iron chelator (Desferal) abrogates artemisinin effect on SERCA.
The first mechanism explains the non-specific effect on various eukaryotic cells (ED50 M). The second one explains the specificity towards Plasmodium falciparum (ED50 nM).
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Spread of chloroquine resistance
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The Mechanism of Accumulation of Chloroquine in the Parasite Food VacuoleChloroquine travels down a pH gradient and inside the parasite becomes diprotonated. This form of the drug (shown in blue) is impermeable to biological membranes.On the right of the figure is a generic structure of a parasite targeted artemisinin derivative
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Hb FP HZ
FP:CQ
CQ
Hb
GluCysGly{ }
NADP
NADPH
GSH
GSSGHMS GR
FP
Fe3+
Fe2+
O2+H+
O2
H2O2
O2+H2O
GSH
GSSG
CQ
GPxReductone
de novosynthesis K+
Na+
Hostcell
Food vacuole
Parasite
1 2
9
10
11
36
8
7
4 5
-
Enzyme
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HV
RS
V H
P
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Table 1. Reported polymorphisms on the Plasmodium falciparum chloroquine resistance transporter gene, pfcrt, on chromosome 7. Wernsdorfer, Curr Opin Infect Dis, 2003, 16, 553-558.