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

1408 Mefloquine
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
History. Mefloquine (LARIAM) is a product of the Malaria Research
Program established by the Walter Reed Institute for Medical
Research in 1963 to develop promising new compounds to
address the alarming growth of drug-resistant malaria. Of the many
4-quinoline methanols tested based on their structural similarity to
quinine, mefloquine displayed high antimalarial activity in animal
models, and emerged from clinical trials as safe and effective against
drug-resistant strains of P. falciparum. Mefloquine was first used to
treat chloroquine-resistant P. falciparum malaria in Thailand.
However, the slow elimination of mefloquine fostered the emergence
of drug-resistant parasites.
Chemistry. The structure of the mefloquine raceme is illustrated in
Figure 49–2. Recent work has demonstrated that the (−)-enantiomer
is associated with adverse CNS effects, whereas the (+)-enantiomer
retains antimalarial activity with fewer side effects. Mefloquine can
be paired with artesunate, thereby reducing the selection pressure
for resistance. This combination has proved efficacious for the treatment
of P. falciparum malaria, even in regions with high prevalence
of mefloquine-resistant parasites.
Mechanisms of Action and Parasite Resistance.
Mefloquine is a highly effective blood schizonticide.
However, it possesses no activity against hepatic stages
or mature gametocytes of P. falciparum or latent tissue
forms of P. vivax.
Earlier work showed that mefloquine associates with intraerythrocytic
hemozoin, suggesting similarities to the mode of action
of chloroquine (Sullivan et al., 1998). However, evidence that this
association might be secondary to a primarily cytosolic mode of
action comes from studies with transgenic P. falciparum lines
expressing different pfmdr1 copy numbers. Increased pfmdr1 copy
numbers are associated with both reduced parasite susceptibility to
mefloquine (and artemisinin) and increased PfMDR1-mediated
solute import into the digestive vacuole of intraerythrocytic parasites
(Rohrbach et al., 2006). Therefore, if the drug’s target resides
outside of this vacuolar compartment, increased import of mefloquine
into the digestive vacuole, potentially driven by PfMDR1
activity, would be beneficial for the parasite and reduce its susceptibility
to the drug.
A comprehensive clinical and molecular epidemiological
study conducted with parasites from Thailand identified pfmdr1 gene
amplification as a major determinant of mefloquine treatment failure
and in vitro mefloquine resistance (Price et al., 2004). Some individuals
in that study nonetheless failed mefloquine treatment despite
not having parasites with multiple pfmdr1 copies, implying secondary
mechanisms of resistance. Mefloquine susceptibility in vitro can
also be affected by the presence of point mutations in pfmdr1 or pfcrt
(Valderramos and Fidock, 2006).
Absorption, Fate, and Excretion. Mefloquine is taken orally because
parenteral preparations cause severe local reactions. The drug is rapidly
absorbed, with marked variability between individuals. Probably
owing to extensive enterogastric and enterohepatic circulation,
plasma levels of mefloquine rise in a biphasic manner to their peak
in ~17 hours. Mefloquine has a variable and long t 1/2
, 13-24 days,
reflecting its high lipophilicity, extensive tissue distribution, and
extensive binding (~98%) to plasma proteins. Mefloquine is extensively
metabolized in the liver. CYP3A4 has been implicated in the
metabolism of mefloquine; this CYP can be inhibited by ketoconazole
and induced by rifampicin (German and Aweeka, 2008).
Excretion of mefloquine is mainly by the fecal route; only ~10% of
mefloquine appears unchanged in the urine. The stereoisomers of
mefloquine exhibit quite different pharmacokinetic characteristics
that relate to their biodisposition (Hellgren et al., 1997).
Therapeutic Uses. Mefloquine should be reserved for the
prevention and treatment of malaria caused by drugresistant
P. falciparum and P. vivax, but it is no longer
considered first-line treatment of malaria in most clinical
contexts. The drug is especially useful as a chemoprophylactic
agent for travelers spending weeks, months, or
years in areas where these infections are endemic
(Table 49–2). In areas where malaria is due to multiply
drug-resistant strains of P. falciparum (particularly in
Southeast Asia), mefloquine is more effective when used
in combination with an artemisinin compound.
Toxicity and Side Effects. The use of mefloquine for the
chemoprophylaxis or treatment of malaria must balance
concerns about clinically significant risks and benefits.
The major adverse effects of mefloquine have been
reviewed in detail (Chen et al., 2006). Mefloquine given
orally is generally well tolerated at chemoprophylactic
dosages, although vivid dreams are common. Significant
neuropsychiatric signs and symptoms can occur in 10%
(or more) of people receiving treatment doses, although
serious adverse events (psychosis, seizures) are rare.
Short-term adverse effects of treatment include nausea,
vomiting, and dizziness. Dividing the dose improves tolerance.
The full dose should be repeated if vomiting
occurs within the first hour.
Estimates for frequency of severe CNS toxicity after mefloquine
treatment can be as high as 0.5%. Adverse reactions include
seizures, confusion or decreased sensorium, acute psychosis, and disabling
vertigo. Such symptoms generally are reversible upon drug discontinuation.
At chemoprophylactic dosages, the risk of serious
neuropsychiatric effects is estimated to be ~0.01% (about the same as
for chloroquine). Mild-to-moderate toxicities (e.g., disturbed sleep,
dysphoria, headache, GI disturbances, and dizziness) occur even at
chemoprophylactic dosages. Whether these symptoms are more common
than with other antimalarial regimens is debated. Adverse effects
usually manifest after the first to third doses and often abate even with
continued treatment. Reports of cardiac abnormalities, hemolysis, and
agranulocytosis are rare.
Contraindications and Interactions. At very high doses, mefloquine
is teratogenic in rodents. Studies have suggested an increased rate of
stillbirths with mefloquine use, especially during the first trimester
(Taylor and White, 2004). The significance of these data has been
debated, but it is fair to say that the evidence for mefloquine’s safety
in pregnancy is not convincing, and mefloquine may be used if it is
the only available treatment option. Pregnancy should be avoided