Biomedical Engineering Reference
In-Depth Information
CH
3
CH
3
H
H
NaBH
4
O
O
O
O
H
3
C
H
3
C
O
O
H
H
O
O
CH
3
CH
3
O
OH
21.8
21.9
CH
3
CH
3
H
H
O
O
O
O
H
3
C
H
3
C
O
O
H
H
O
O
CH
3
O
CH
3
O
O
OH
R
O
21.10
R=CH
3
21.11
R=CH
2
CH
3
21.12
FIGURE 21.10
Treatment of artemisinin (
21.8
) with sodium borohydride selectively reduces the ester to
the semiacetal dihydroartemisinin (
21.9
). The semiacetal can be converted into the lipid-soluble artemether
(
21.10
) or arteether (
21.11
). Monoesterii cation with dicarboxylic acids results in the formation of water-
soluble esters of the hemiacetal, e.g., artesunate (
21.12
).
Fe
3+
CH
3
CH
3
Fe
2+
CH
3
.
H
H
H
H
2
C
H
+
O
O
-
H
3
C
H
3
C
HO
O
O
.
O
O
O
H
H
H
Fe
2+
O
O
O
CH
3
CH
3
CH
3
CH
3
O
O
O
21.8
SCHEME 21.1
Possible reductive scission of the peroxide bond of artemisinin to give a reactive carbon
centerd radical.
Both pumps are inhibited by the sesquiterpene lactone thapsigargin, but
Pf
ATP6 only by artemisi-
nin and analogs. A mutation of Leu263 into Glu in
Pf
ATP6 preserves thapsigargin but abolish
artemisinin sensitivity. Very recent results, however, question the effect of artemisinin on
Pf
ATP6.
The poor solubility of artemisin allows only oral or rectal administration of the drug. Since oral
administration is impossible for severely sick patients, lipid-soluble derivatives (artemether [
21.10
], and
arteether [
21.11
]) and water-soluble derivatives (e.g., artesunate [
21.12
]) have been developed by selec-
tive reduction of the ester carbonyl group followed by ether or ester formation (refer to Figure 21.10).
To avoid recrudescense (reappearance of a disease after it has been quiescent), artemisinin and
artemisinin derivatives are preferentially given in combination therapy. Some examples of combination
therapies are artesunate in combination with chlorproguanil and dapsone (
21.34
) (refer to Figure 21.18),
artesunate in combination with mel oquine (
21.27
) (refer to Figure 21.15), and artesunate in combination
with sulphadoxine (
21.33
) (refer to Figure 21.18) and pyrimethamine (
21.31
) (refer to Figure 21.16).
