DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1402 chloroquine and pyrimethamine-sulfadoxine resistant
strains of P. falciparum found in sub-Saharan Africa.
Proguanil is effective and tolerated well in combination
with atovaquone, once daily for 3 days, to treat
drug-resistant strains of P. falciparum or P. vivax (see
section on atovaquone). Indeed, this drug combination
has been successful in Southeast Asia, where highly
drug-resistant strains of P. falciparum prevail. P. falciparum
readily develops clinical resistance to monotherapy
with either proguanil or atovaquone; however
resistance to the combination is uncommon unless the
strain is initially resistant to atovaquone. In contrast,
some strains resistant to proguanil do respond to
proguanil plus atovaquone.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Toxicity and Side Effects. In chemoprophylactic doses of 200-300 mg
daily, proguanil causes relatively few adverse effects, except occasional
nausea and diarrhea. Large doses (≥1 g daily) may cause vomiting,
abdominal pain, diarrhea, hematuria, and the transient
appearance of epithelial cells and casts in the urine. Gross accidental
or deliberate overdose (as much as 15 g) has failed to produce
lasting sequelae. Doses as high as 700 mg twice daily have been
taken for >2 weeks without serious toxicity. Proguanil is considered
safe for use during pregnancy. It is remarkably safe when used in
conjunction with other antimalarial drugs such as chloroquine, atovaquone,
tetracyclines, and other antifolates.
QUINOLINES AND RELATED COMPOUNDS
Quinolines have been the mainstay of antimalarial
chemotherapy starting with quinine nearly 400 years
ago. In the last century, legions of related compounds
were synthesized and tested for antimalarial activity.
These efforts produced several drugs for the chemoprophylaxis
and treatment of malaria. The most important
of these are shown in Figure 49–2.
Chloroquine and Hydroxychloroquine
History. Chloroquine (ARALEN) is one of a large series of 4-aminoquinolines
synthesized as part of the extensive cooperative program
of antimalarial research in the U.S. during World War II.
Chloroquine proved most promising and was released for field trial.
When hostilities ceased, it was discovered that the compound had
been synthesized and studied as early as 1934 under the name of
Resochin at the Bayer laboratories in Germany but had been rejected
because of toxicity in avian models.
Chemistry. The d-, l-, and dl- forms of chloroquine (see structure in
Figure 49–2) have equal potency against P. lophurae malaria (a duck
parasite), but the d-isomer is somewhat less toxic than the l-isomer
in mammals. A chlorine atom attached to position 7 of the quinoline
ring confers the most potent antimalarial activity in both avian and
human malarias. Research on the structure-activity relationships of
chloroquine and related alkaloid compounds continues in an effort to
find new effective antimalarials with improved safety profiles that can
be used successfully against chloroquine- and multidrug-resistant
strains of P. falciparum. One example is the synthesis of short-chain
derivatives that can demonstrate full efficacy against chloroquineresistant
strains of P. falciparum. Another important example is piperaquine,
a bisquinoline that was extensively used in China to treat
chloroquine-resistant malaria. It is highly efficacious in combination
with dihydroartemisinin (Davis et al., 2005); see earlier section on
artemisinin-based combination therapies.
Hydroxychloroquine, in which one of the N-ethyl substituents
of chloroquine is β-hydroxylated, is essentially equivalent to chloroquine
against P. falciparum malaria. This analog is preferred over
chloroquine for treatment of mild rheumatoid arthritis and lupus erythematosus
because, in the high doses required, it may cause less
ocular toxicity. Care should be taken when these compounds are
administered to patients with known G6PD deficiency.
Mechanisms of Action and Resistance. Asexual malarial
parasites flourish in host erythrocytes by digesting
hemoglobin in their acidic digestive vacuoles, a
process that generates free radicals and iron-bound
heme (ferriprotoporphyrin IX) as highly reactive byproducts
(Goldberg, 2005). Perhaps aided by histidinerich
proteins and lipids, heme is sequestered as an
insoluble, chemically inert malarial pigment termed
hemozoin. Many theories for the mechanism of action
of chloroquine have been advanced (Valderramos and
Fidock, 2006). Current evidence suggests that quinolines
interfere with heme detoxification. Chloroquine,
a weak base, concentrates in the highly acidic digestive
vacuoles of susceptible Plasmodium, where it binds to
heme and disrupts its sequestration. Failure to inactivate
heme or even enhanced toxicity of drug-heme
complexes is thought to kill the parasites via oxidative
damage to membranes, digestive proteases, or other
critical biomolecules. Other quinolines such as quinine,
amodiaquine, and mefloquine, as well as other
amino alcohol analogs (lumefantrine, halofantrine) and
mannich base analogs (pyronaridine), may act by a
similar mechanism, although differences in their
actions have been proposed (Bray et al., 2005; Eastman
and Fidock, 2009).
Resistance of erythrocytic asexual forms of P. falciparum to
antimalarial quinolines, especially chloroquine, now is common in
most parts of the world (Figure 49–3). Reports of chloroquine failures
in the treatment of P. vivax are fairly common in Indonesia, East
Timor, and Papua New Guinea, in which case alternative treatments
(mefloquine, or quinine plus doxycycline or tetracycline, or
atovaquone-proguanil) should be considered (Price et al., 2009).
Chloroquine-resistant P. vivax has also been recently detected in
Ethiopia, where P. vivax is an important cause of morbidity
(Yeshiwondim et al., 2010). Chloroquine-resistant P. vivax isolates
do not appear to have significant alterations in their pfcrt ortholog
and may have a different resistance mechanism.