trans

TREATMENT OF PARASITIC DISEASES 443
also to the release of insulin from pancreatic
-cells by quinine.
Intravenous quinidine or quinine can produce
severe myocardial depression, hypotension,
prolonged QT interval and/or ventricular
arrhythmia if infused too rapidly. They can
result in respiratory depression in persons
with myasthenia gravis. In addition, quinine
stimulates uterine contraction during pregnancy
and can precipitate abortion.
Chloroquine
Chloroquine (Figure 17.1) remains the drug
of choice for the prophylaxis and treatment
of malaria in the few remaining areas of the
world where resistance has not yet emerged.
It is active only against the erythrocytic stages
of the parasite. Chloroquine accumulates in
the acidic vesicles of Plasmodium species. It
inhibits plasmodial heme polymerase, an
enzyme that polymerizes and thereby detoxifies
ferriprotoporphyrin IX, a potentially toxic
breakdown product of hemoglobin. The result
is an increase in the concentration of this toxic
molecule and death of the parasite. Resistance
occurs by parasite-mediated transport of
chloroquine from malaria-infected erythrocytes.
In P. falciparum, chloroquine resistance
is linked to multiple mutations in PfCRT, a
protein that appears to function as a transporter
in the parasite’s digestive vacuolar
membrane. Rapid diagnostic assays have
been employed as surveillance tools to detect
chloroquine resistance in the field. The transport
of chloroquine out of parasite-infected
erythrocytes can be blocked by calcium channel
inhibitors, but not at concentrations that
can be safely attained in humans. Chloroquineresistant
P. vivax isolates appear to differ in
their mechanism of resistance.
Chloroquine’s long half-life, approximately
7 days, permits once weekly administration.
It is generally very well tolerated, but the drug
has a bitter taste and can cause gastrointestinal
symptoms. It has been associated with exacerbation
of psoriasis and other dermatoses.
Retinal degeneration has been reported with
high doses administered for the treatment of
collagen vascular diseases, but it rarely if ever
occurs with doses recommended for malaria
prophylaxis or treatment.
Unfortunately, resistance to chloroquine has
become widespread among P. falciparum and is
now well documented in P. vivax in some areas.
Only in Latin America west and north of the
Panama Canal Zone, Haiti and the Dominican
Republic and in some areas of the Middle East
can P. falciparum be presumed to be sensitive.
Terminal treatment with primaquine is needed
in persons infected with P. vivax or P. ovale who
are treated with chloroquine to prevent relapses.
Mefloquine
Mefloquine (Figure 17.1), like chloroquine, is
only active against the erythrocytic stages of
Plasmodium species. Despite being a quinine
derivative, the precise mechanism of mefloquine’s
action is not known. It cannot be
assumed to be the same as that of chloroquine.
Mefloquine is concentrated in membranes
and may interfere with the parasite’s food vacuole.
It has a long half-life, ranging from 6 to
23 days, and is administered weekly for prophylaxis.
Higher doses are used for the treatment
of acute malaria. Mefloquine resistance
is now prevalent in the rural rim of Thailand
and in adjacent areas of Southeast Asia. It has
been reported in the Amazon River basin and
elsewhere.
The biggest problem with mefloquine is its
side-effects. The drug has neurostimulatory
activity and frequently produces vivid dreams.
It can result in seizures in persons with a history
of epilepsy. Although not frequent, serious
MEDICAL APPLICATIONS